Antitumoral compounds

ABSTRACT

New spisulosine derivatives of use in treating tumors are of the formula (I) wherein: each X is the same or different, and represents H, OH, OR′, SH, SR′, SOR′, SO 2 R′, NO 2 , NH 2 , NHR′, N(R′) 2 , CN, halogen, C(═O)H, C(═O)CH 3 , CO 2 H, CO 2 CH 3 , substituted or unsubstituted C 1 -C 18  alkyl, substituted or unsubstituted C 2 -C 18  alkenyl, substituted or unsubstituted C 2 -C 18  alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaromatic, or two groups X may together form ═O; Y is NR 1 , OR 1 , PR 1 , SR 1 , or halogen, wherein the number of substituents R 1  is selected to suit the valency and each R 1  is independently selected of H, OH, C(═O)R′, P(═O)R′R″, substituted or unsubstituted C 1 -C 18  alkyl, substituted or unsubstituted C 2 -C 18  alkenyl, substituted or unsubstituted C 2 -C 18  alkynyl, substituted or unsubstituted aryl, and wherein the dotted line indicates an optional double bond; each Z is the same different, and represents H, OH, OR′, SH, SR′, SOR′, SO 2 R′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHC(O)R′, CN, halogen, C(═O)H, C(═O)CH 3 , CO 2 H, CO 2 CH 3 , substituted or unsubstituted C 1 -C 18  alkyl, substituted or unsubstituted C 2 -C 18  alkenyl, substituted or unsubstituted C 2 -C 18  alkenyl, substituted or unsubstituted C 2 -C 18  alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaromatic, or two groups Z may together form ═O; z is 0 to 25; y is to 0 to 20; R 2  is H, C(═O)R′, P(═O)R′R″, S(═O)R′R″, S(═O) 2 R′, substituted or unsubstituted C 1 -C 18  alkyl, substituted or unsubstituted C 2 -C 18  Alkenyl, substituted or unsubstituted C 2 -C 18  alkynyl, substituted or unsubstituted aryl; R 3  is H, C(═O)R′, P(═O)R′R″, S(═O)R′R″, S(═O) 2 R′, substituted or unsubstituted C 1 -C 18  alklyl, substituted or unsubstituted C 2 -C 18  alkenyl, substituted or unsubstituted C 2 -C 18  alkynyl, substituted or unsubstituted aryl; each of the R′, R″ groups is independently selected from the group consisting of H, OH, NO 2 , NH 2 , SH, CN, halogen, ═O, C(═O)H, C(═O)CH 3 , CO 2 H, CO 2 CH 3 , substituted or unsubstituted C 1 -C 18  alkyl, substituted or unsubstituted C 1 -C 18  alkoxy, substituted or unsubstituted C 2 -C 18  alkenyl, substituted or unsubstituted C 2 -C 18  alkynl, substituted or unsubstituted aryl; there may be one or more unsaturations in the hydrocarbon backbone defined by the chain (II) and salts thereof; with the exception of a C 16 -C 24  2-amino-3-hydroxyalkane or a C 16 -C 24  2-amino-3-hydroxyalkene.

[0001] The present invention relates to new antitumoral derivatives ofspisulosine-285.

BACKGROUND OF THE INVENTION

[0002] Spisulosine 285 is a bioactive compound that has been found topossess specific antitumor activity, described in the InternationalPatent WO 99/52521. In the same patent specification are also describedsphingoid-type bases spisulosines 299 and 313 and some sphingosineanalogs.

[0003] 1 (spisulosine-285) n=14

[0004] 2 (spisulosine-299) n=15

[0005] 3 (spisulosine-313) n=16

[0006] sphingosine, n=12 and

[0007] nonadeca-4-sphingenine, n=13; and

[0008] Spisulosines 285, 299 and 313 were isolated from Spisulapolynyma, an edible clam originally isolated from samples found off thecoast of Japan. The compound we call spisulosine 285 and the syndiastereoisomer were first synthetized by Croatian researchers in thedetermination of absolute configurations of lipid bases with two or moreasymmetric carbon atoms (Prostenik, M.; Alaupovic, P. Croat. Chem. Acta.1957, 29, 393).

SUMMARY OF THE INVENTION

[0009] The present invention is directed to analogs of the spisulosinefamily having the following formulae I and II:

[0010] Wherein the substituent groups defined by R₁, R₂ and R₃ are eachindependently selected of H, C(═O)R′, P(═O)R′R″, S(═O)R′R″, substitutedor unsubstituted C₁-C₁₈ alkyl, substituted or unsubstituted C₂-C₁₈alkenyl, substituted or unsubstituted C₂-C₁₈ alkynyl, substituted orunsubstituted aryl. Wherein each of the R′, R″ groups is independentlyselected from the group consisting of H, OH, NO₂, NH₂, SH, CN, halogen,═O, C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈alkyl, substituted or unsubstituted C₂-C₁₈ alkenyl, substituted orunsubstituted C₂-C₁₈ynyl, substituted or unsubstituted aryl.

[0011] R₂ can be independently an internal salt. Preferred internalsalts are formed using any kind of mineral or organic acid such ashydrochloric acid, hydrobromic acid, tartaric acid, succinic acid, etc.

[0012] Wherein the substituent groups defined by X₁, X₂ and X₃ areindependently selected of H, OH, OR′, SH, SR′, SOR′, SO₂R′, NO₂, NH₂,NHR′, N(R′)₂, NHC(O)R′, CN, halogen, ═O, C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃,substituted or unsubstituted C₁-C₁₈ aLkyl, substituted or unsubstitutedC₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaromatic.Wherein substituent groups defined by R′ are each independently selectedfrom the group consisting of H, OH, OR′, SH, SR′, SOR, SO₂R′, NO₂, NH₂,NHR′, N(R′)₂, NHC(O)R′, CN, halogen, ═O, C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃,substituted or unsubstituted C₁-C₁₈ aLkyl, substituted or unsubstitutedC₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaromatic.

[0013] Wherein x and y can be between 0 and 20. Preferably x is in therange 8 to 16, more preferably 10, 11, 12, 13 or 14. Preferably y is 0,1 or 2. Currently the most preferred is that x is 11, 12 or 13, and y is0 or 1.

[0014] Wherein the dotted line is one or several double bonds placed inany particular position of the side chain.

[0015] Wherein the stereochemistry of the groups OR₁ and NR₂R₃ informula I can be independently syn or anti.

[0016] Wherein the group defined by Y in formula II is independentlyselected from the group consisting of N, O, P, S, halogen. Wherein thedotted line is a single or double bond. Wherein R₁ is independentlyselected of H, C(═O)R′, P(═O)R′R″, S(═O)R′R″, substituted orunsubstituted C₁-C₁₈ alkyl, substituted or unsubstituted C₂-C₁₈ alkenyl,substituted or unsubstituted C₂-C₁₈ alkynyl, substituted orunsubstituted aryl. Wherein each of the R′, R″ groups is independentlyselected from the group consisting of H, OH, NO₂, NH₂, SH, CN, halogen,═O, C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈alkyl, substituted or unsubstituted C₂-C₁₈ alkenyl, substituted orunsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl.

[0017] In one aspect, we provide compounds of the formula I:

[0018] Wherein the substituent groups defined by R₁, R₂ and R₃ are eachindependently selected of H, C(═O)R′, substituted or unsubstitutedC₁-C₁₈ alkyl, substituted or unsubstituted C₂-C₁₈ alkenyl, substitutedor unsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl.

[0019] R₂ can be independently an internal salt. Preferred internalsalts are formed using any kind of mineral or organic acid such ashydrochloric acid, hydrobromic acid, tartaric acid, succinic acid, etc.

[0020] Wherein each of the R′ groups is independently selected from thegroup consisting of H, OH, NO₂, NH₂, SH, CN, halogen, ═O, C(═O)H,C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈ aLkyl,substituted or unsubstituted C₂-C₁₈ alkenyl, substituted orunsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl.

[0021] Wherein X₁, X₂ and X₃ are independently selected of H, OH, OR′,SH, SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′, N(RW)₂, NHC(O)R′, CN, halogen, ═O,C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈alkyl, substituted or unsubstituted C₂-C₁₈ alkenyl, substituted orunsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaromatic.

[0022] Wherein substituent groups defined by R′ are each independentlyselected from the group consisting of H, OH, OR′, SH, SR′, SOR′, SO₂R′,NO₂, NH₂, NHR′, N(R′)₂, NHC(O)R′, CN, halogen, ═O, C(═O)H, C(═O)CH₃,CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈ alkyl, substituted orunsubstituted C₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaromatic.

[0023] Wherein x and y can be between 0 and 20.

[0024] Wherein the dotted line is one or several double bonds placed inany particular position of the side chain.

[0025] Wherein the stereochemistry of the groups OR₁ and NR₂R₃ can beindependently syn or anti.

[0026] Suitable halogen substituents in the compounds of the presentinvention include F, Cl, Br and I.

[0027] Alkyl groups preferably have from 1 to about 12 carbon atoms,more preferably 1 to about 8 carbon atoms, still more preferably 1 toabout 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms.Methyl, ethyl and propyl including isopropyl are particularly preferredalkyl groups in the compounds of the present invention. As used herein,the term alkyl, unless otherwise modified, refers to both cyclic andnoncyclic groups, although cyclic groups will comprise at least threecarbon ring members.

[0028] Preferred alkenyl and alkynyl groups in the compounds of thepresent invention have one or more unsaturated linkages and from 2 toabout 12 carbon atoms, more preferably 2 to about 8 carbon atoms, stillmore preferably 2 to about 6 carbon atoms, even more preferably 1, 2, 3or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refer toboth cyclic and noncyclic groups, although straight or branchednoncyclic groups are generally more preferred.

[0029] Preferred alkoxy groups in the compounds of the present inventioninclude groups having one or more oxygen linkages and from 1 to about 12carbon atoms, more preferably from 1 to about 8 carbon atoms, and stillmore preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3or 4 carbon atoms.

[0030] Preferred alkylthio groups in the compounds of the presentinvention have one or more thioether linkages and from 1 to about 12carbon atoms, more preferably from 1 to about 8 carbon atoms, and stillmore preferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2,3 or 4 carbon atoms are particularly preferred.

[0031] Preferred alksulfinyl groups in the compounds of the presentinvention include those groups having one or more sulfoxide (SO) groupsand from 1 to about 12 carbon atoms, more preferably from 1 to about 8carbon atoms, and still more preferebly 1 to about 6 carbon atoms.Alkylsulfinyl groups having 1, 2 3 or 4 carbon atoms are particularlypreferred.

[0032] Preferred alkylsulfonyl groups in the compounds of the presentinvention include those groups having one or more sulfonyl (SO2) groupsand from 1 to about 12 carbon atoms, more preferably from 1 to about 8carbon atoms, and still more preferably 1 to about 6 carbon atoms.Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularlypreferred.

[0033] Preferred aminoalkyl groups include those groups having one ormore primary, secondary and/or tertiary amine groups, and from 1 toabout 12 carbon atoms, more preferably 1 to about 8 carbon atoms, stillmore preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3or 4 carbon atoms. Secondary and tertiary amine groups are generallymore preferred than primary amine moieties.

[0034] Suitable heteroaromatic groups in the compounds of the presentinvention contain one, two or three heteroatoms selected from N, O or Satoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinylincluding 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, fLryl, pyrrolyi,thienyl, thiazolyi, oxazolyl, imidazolyl, indolyl, benzofuranyl andbenzothiazolyl. Suitable heteroalicyclic groups in the compounds of thepresent invention contain one, two or three heteroatoms selected from N,O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, morpholino and pyrrolindinyl groups.

[0035] Suitable carbocyclic aryl groups in the compounds of the presentinvention include single and multiple ring compounds, including multiplering compounds that contain separate and/or fused aryl groups. Typicalcarbocyclic aryl groups contain 1 to 3 separate or fused rings and from6 to about 18 carbon ring atoms. Specifically preferred carbocyclic arylgroups include phenyl including substituted phenyl such as 2-substitutedphenyl, 3-substituted phenyl, 2, 3-substituted phenyl, 2,5-substitutedphenyl, 2,3,5-substituted and 2,4,5-substituted phenyl, including whereone or more of the phenyl substituents is an electron-withdrawing groupsuch as halogen, cyano, nitro, alkanoyl, sulfinyl, sulfonyl and thelike; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl;phenanthryl; and anthracyl.

[0036] References herein to substituted R′ groups in the compounds ofthe present invention refer to the specified moiety that may besubstituted at one or more available positions by one or more suitablegroups, e.g., halogen such as fluoro, chloro, bromo and iodo; cyano;hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such asacyl and the like; carboxamido; alkyl groups including those groupshaving 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms andmore preferably 1-3 carbon atoms; alkenyl and alkynyl groups includinggroups having one or more unsaturated linkages and from 2 to about 12carbon or from 2 to about 6 carbon atoms; alkoxy groups having thosehaving one or more oxygen linkages and from 1 to about 12 carbon atomsor 1 to about 6 carbon atoms; aryloxy such as phenoxy; aikylthio groupsincluding those moieties having one or more thioether linkages and from1 to about 12 carbon atoms or from 1 to about 6 carbon atoms;alkylsulfinyl groups including those moieties having one or moresulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about6 carbon atoms; alkylsulfonyl groups including those moieties having oneor more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1to about 6 carbon atoms; aminoalkyl groups such as groups having one ormore N atoms and from 1 to about 12 carbon atoms or from 1 to about 6carbon atoms; carbocylic aryl having 6 or more carbons, particularlyphenyl (e.g., R being a substituted or unsubstituted biphenyl moiety);and aralkyl such as benzyl. Substituent groups may themselves besubstituted, as in a trifluoromethylcinnamoyl group or an aminoacid acylgroup such as with valine or Boc-valine.

[0037] 1. The present invention notably provides compounds of formula:

[0038] wherein:

[0039] each X is the same or different, and represents H, OH, OR′, SH,SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′, N(R′)₂, NHC(O)R′, CN, halogen, C(═O)H,C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈ alkyl,substituted or unsubstituted C₂-C₁₈ alkenyl, substituted orunsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaromatic, or two groups X maytogether form ═O;

[0040] Y is NR₁, OR₁, PR₁, SR₁, or halogen, wherein the number ofsubstituents R₁ is selected to suit the valency and each R₁ isindependently selected of H, OH, C(═O)R′, P(═O)R′R″, S(═O)R′R″,substituted or unsubstituted C₁-C₁₈ alkyl, substituted or unsubstitutedC₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈ alkynyl, substitutedor unsubstituted aryl, and wherein the dotted line indicates an optionaldouble bond such that Y can also be ═O or ═N—OH or the group Y withNR₂R₃ and the intervening atoms can form a heterocycle;

[0041] each Z is the same or different, and represents H, OH, OR′, SH,SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′, N(R′)₂, NHC(O)R′, CN, halogen, C(═O)H,C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈ alkyl,substituted or unsubstituted C₂-C₁₈ alkenyl, substituted orunsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaromatic, or two groups Z maytogether form ═O;

[0042] z is 0 to 25;

[0043] y is 0 to 20;

[0044] R₂ and R₃ are the same or different and each is H, C(═O)R′,C(=S)R′, P(═O)R′R″, S(═O)R′R″, S(═O)2R′, substituted or unsubstitutedC₁-C₁₈ alkyl, substituted or unsubstituted C₂-C₁₈ alkenyl, substitutedor unsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl;

[0045] each of the R′, R″ groups is independently selected from thegroup consisting of H, OH, NO₂, NH₂, NHR′, NR′R″, SH, CN, halogen, ═O,C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈alkyl, substituted or unsubstituted C₁-C₁₈ alkoxy, substituted orunsubstituted C₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈allynyl, substituted or unsubstituted aryl;

[0046] there may be one or more unsaturations in the hydrocarbonbackbone defined by the chain:

[0047] and salts thereof.

[0048] Typically each X is H.

[0049] Typically Y is NR₁, OR₁, PR₁, or halogen, wherein the number ofsubstituents R₁ is selected to suit the valency and each R₁ isindependently selected of H, C(═O)R′, P(═O)R′R″, substituted orunsubstituted C₁-C₁₈ alkyl, and wherein the dotted line indicates anoptional double bond such that Y can also be ═O or ═N—OH, or the group Ywith NR₂R₃ and the intervening atoms can form a heterocycle.

[0050] Typically Z represents H, NH₂, NHR′, N(R′)₂, halogen, substitutedor unsubstituted C₁-C₁₈ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaromatic.

[0051] Typically z is 10 to 20.

[0052] Typically is 0 to 4.

[0053] Typically R₂ and R₃ are the same or different and each is H,C(═O)R′, C(=S)R′, S(═O)R′R″, S(═O)₂R′, substituted or unsubstitutedC₁-C₁₈ alkyl;

[0054] Each of the R′, R″ groups is independently selected from thegroup consisting of H, OH, NO₂, NH₂, NHR′, NR′R″, SH, CN, halogen, ═O,C(═O)H, C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈alkyl, substituted or unsubstituted C₁-C₁₈ aLkoxy, substituted orunsubstituted C₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈alkynyl, substituted or unsubstituted aryl, the selection of respectiveclasses of defintions being made as appropriate to suit the preferreddefintions given subsequently.

[0055] Compounds of this invention extend to salts, notablypharmaceutically acceptable salts. Such salts may be formed with organicor inorganic acids, and examples are given in this text.

[0056] In one class of compounds of this invention, the hydrocarbonbackbone defined by the chain:

[0057] is of the formula:

[0058] where x is 0 to 20 and the dotted line indicates one or moredouble bonds in the backbone. For example there can a double bond at theposition shown by the dotted line. For example, the hydrocarbon backboneis of the formula:

[0059] where x and y are as defined.

[0060] A preferred group of compounds of this invention include thosewherein the terminal group —C(X)₃ is —hCH₃.

[0061] In another preferred class, there are no unsaturations in thehydrocarbon backbone.

[0062] For preference, z is from 10 to 19.

[0063] Suitable compounds include those where Y is OH, O(C═O)R′ where R′is optionally halogen-substituted alkyl, OR′ where R′ is alkyl, halogen,OP(═O)R′₂ where R′ is alkoxy, NH₂, ═O, ═NOH, or the group Y when OH withNR₂R₃ and the intervening atoms form a heterocycle of formula:

[0064] If desired, R₂ and R₃ are the same. Typically at least one of R₂and R₃ is alkyl; alkyl substituted by aryl; hydrogen; C(═O)R′ where R′is alkyl or alkoxy, halogen-substituted alkyl, optionally substitutedamino-substitued alkyl, aryloxy, alkoxy, optionally substitutedaryl-substituted alkenyl; (C═S)NHR′ where R′ is aryl; (C═O)NHR′ where R′is aryl or alkyl; SO₂R′ where R′ is alkyl, or (C═O)R′ where R′ isoptionally substituted aminoalkyl thereby giving an optionallysubstituted aminoacid acyl group.

[0065] In preferred compounds, y is 0 to 3.

[0066] The terminal group —C(Z)₃ can be —CH₃.

[0067] The stereochemistry is usually:

[0068] Notable preferred compounds meet two or more of the followingcriteria:

[0069] (a) the terminal group —C(X)₃ is —CH₃;

[0070] (b) z is 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19

[0071] (c) the hydrocarbon backbone is of the formula:

[0072] where x is 12;

[0073] (d) Y is OR₁ where R₁ is H, methyl, acetyl, PO(OMe)2, COCF3 or Yis Cl, NH₃ ⁺Cl—, ═O, ═NOH;

[0074] (e) R₂ and R₃ are independently selected from the groupconsisting of H, methyl, acetyl, benzyl, Boc, CSNHPh, CONHPh,CONH^(n)Bu, SO₂Me, COCF₃, COCH═CHPh, COCH═CHPhCF₃, COC₁₅H₃₂,COCH(NHBoc)CHMe₂, COCH(NH₃ ⁺Cl⁻)CHMe₂;

[0075] (f) y is 0, 1, 2 or 3;

[0076] (g) Z is the same or different, and represents H, F, methyl,ethyl, hydroxyphenyl, amino, dibenzylamino or NH₃Cl;

[0077] (h) the stereochemistry is

[0078] or

[0079] (i) the compound or salt is in the form of a salt.

[0080] At least one of the following criteria can apply:

[0081] (j) z is not 12, 13 or 14;

[0082] (k) Y is not OH;

[0083] (l) at least one of R₂ and R₃ is not hydrogen;

[0084] (m) y is at least 1;

[0085] (n) at least one Z is not hydrogen;

[0086] (o) the compound or salt is in the form of a salt.

[0087] Preferred combinations of these criteria include (k) with (l),(k) with (n), (l) with (n), any of these with (i), any of these with(a), any of these with (b). Other preferred combinations which may betaken with or without these combinations include (d) taken with (k), (e)taken with (l), (g) taken with (n).

[0088] A preferred class of compounds is of the formula:

[0089] where

[0090] z is 10 to 19;

[0091] Y is OR₁ where R₁ is H, methyl, acetyl, PO(OMe)₂, COCF₃ or Y isCl, NH₃ ⁺Cl⁻, ═O, ═NOH;

[0092] R₂ and R₃ are independently selected from the group consisting ofH, methyl, acetyl, benzyl, Boc, CSNHPh, CONHPh, CONH^(n)Bu, SO₂Me,COCF₃, COCH═CHPh, COCH═CHPhCF₃, COC₁₅H₃₂, COCH(NHBoc)CHMe₂, COCH(NH₃⁺Cl⁻)CHMe₂;

[0093] Z represents H, F, methyl, ethyl, hydroxyphenyl, amino,dibenzylamino or NH₃Cl.

[0094] Typical compounds of this invention include the following:

[0095] Antitumoral activities of these compounds include leukaemias,lung cancer, colon cancer, kidney cancer, prostate cancer, ovariancancer, breast cancer, sarcomas and melanomas.

[0096] Another especially preferred embodiment of the present inventionis pharmaceutical compositions useful as antitumor agents which containas active ingredient a compound or compounds of the invention, includingsalts, as well as the processes for their preparation.

[0097] Examples of pharmaceutical compositions include any solid(tablets, pills, capsules, granules etc.) or liquid (solutions,suspensions or emulsions) with suitable composition or oral, topical orparenteral administration.

[0098] Administration of the compounds or compositions of the presentinvention may be any suitable method, such as intravenous infusion, oralpreparation, intraperitoneal and intravenous preparation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0099] The compounds of the present invention can be preparedsynthetically. The present invention includes the synthetic processesdescribed in the following schemes. Scheme 1 illustrates the preparationof the different aldehydes used as starting materials for the synthesisof spisulosine derivatives.

[0100] Scheme 2 shows the preparation of spisulosine derivatives havingthe (2S,3R) configuration using the aldehyde derived from thecorresponding L-aminoacid and Grignard reagents of different lengths.

[0101] Scheme 3 describes the synthesis of the enantiomeric form of thefinal products of spisulosine starting from the corresponding D-alaninederivative.

[0102] The methods for the synthesis of N-acetyl, O-methyl,3-halo-3-deoxy and O-phosphate derivatives of spisulosine are outlinedin Scheme 4.

[0103] Scheme 5 shows the preparation of the corresponding (2S,3S)diastereoisomers of spisulosine, in which the final diamine is preparedvia the azide intermediate. Preparation of the diastereoisomeric form ofthis diamine is outlined in Scheme 6.

[0104] In addition, the methods for the synthesis of O-acetyl andO-trifluoroacetyl derivatives of spisulosine are shown in Scheme 6.

[0105] Other Spisulosines 285 and 299 derivatives are prepared followingdifferent procedures which are described in Scheme 7.

[0106] 3-Keto derivatives of spisulosine and their corresponding oximescan be prepared as described in Scheme 8.

[0107] The enantiomeric form of ketone 126 is prepared from theappropriate aminoalcohol as indicated in Scheme 9.

[0108] The synthesis of the 1-fluoro derivative of spisulosine startingfrom D-erythrosphingosine is depicted in Scheme 10.

TABLE 1 Cytotoxicity of Spisulosine Analogs (IC50, Molar) Compound MWP388 A549 HT29 MEL28 DU145

285.51 3.50E−08 3.50E−08 3.50E−08 1.75E−07 3.50E−08

299.53 3.34E−08 3.34E−08 3.34E−08 3.34E−08 3.34E−08

313.56 3.19E−08 3.19E−08 3.19E−08 3.19E−07 3.19E−08

229.40 4.36E−07 2.18E−06 4.36E−07 2.18E−06 2.18E−06

243.43 4.11E−07 4.11E−07 4.11E−07 2.05E−06 4.11E−07

257.46 3.88E−07 1.94E−07 3.88E−07 3.68E−07 1.94E−07

293.92 3.40E−09 3.40E−09

451.73 NA NA NA NA NA

271.48 3.68E−08 3.68E−08 3.68E−08 3.68E−08 3.68E−08

307.94 3.25E−08 3.25E−08

360.55 2.77E−08 2.77E−08 2.77E−08 2.77E−08 2.77E−08

321.97 3.11E−08 3.11E−08 1.55E−08 3.11E−07 3.11E−08

479.78 NA NA NA NA NA

336.00 2.98E−08 2.98E−08

493.81 NA NA NA NA NA

350.02 1.43E−08 1.43E−08

327.59 1.53E−07 3.05E−07 3.05E−07 3.05E−07 3.05E−07

364.05 2.75E−08 2.75E−08

341.61 2.93E−07 NA 1.46E−06 NA 1.46E−06

355.64 1.41E−06 NA 2.81E−06 NA 2.81E−06

285.51 3.50E−09 3.50E−09

321.97 1.55E−08 1.55E−08

299.53 3.34E−08 3.34E−08 3.34E−08 3.34E−07 3.34E−08

336.00 2.98E−09 2.98E−09

313.56 3.19E−07 3.19E−07

350.02 2.86E−08 2.86E−08

327.59 3.05E−08 3.05E−08

364.05 2.75E−08 2.75E−08

313.56 1.59E−07 1.59E−07

350.02 2.86E−08 2.86E−08

313.56 NA NA

350.02 NA NA

364.05 NA NA

377.60 1.32E−06 1.32E−06

414.06 2.42E−07 2.42E−07

328.58 1.52E−06 1.52E−06

401.50 1.24E−06 1.24E−06

285.51 3.50E−07 3.50E−07 3.50E−07 3.50E−07 3.50E−07

327.55 NA NA NA NA NA

299.53 1.67E−06 1.67E−06

303.95 3.29E−07 3.29E−07 3.29E−07 3.29E−07 3.29E−07

393.54 1.27E−06 1.27E−06 1.27E−06 1.27E−06 1.27E−06

285.51 3.50E−07 3.50E−07 3.50E−07 3.50E−07 3.50E−07

299.53 3.34E−07 3.34E−07 3.34E−07 3.34E−07 3.34E−07

357.44 1.40E−06 1.40E−06

385.62 NA NA

495.54 2.02E−08 2.02E−08

427.66 NA NA NA NA NA

364.01 2.75E−07 2.75E−07 1.37E−07 2.75E−07 1.37E−07

357.44 2.80E−07 2.80E−07

313.56 3.19E−07 3.19E−07 3.19E−07 3.19E−07 3.19E−07

299.53 3.34E−07 3.34E−07 3.34E−07 3.34E−07 3.34E−07

420.70 NA NA NA NA NA

404.63 NA NA

384.64 NA NA

363.60 2.75E−08 2.75E−08

377.63 2.65E−07 2.65E−07

395.54 NA NA

477.52 NA NA

395.54 NA NA

415.65 NA NA

483.65 NA NA

539.96 NA NA

484.76 NA NA

421.10 NA NA

305.93 1.63E−07 1.63E−07 1.63E−07 3.27E−07 1.63E−07

319.95 3.13E−08 1.56E−07 3.13E−08 1.56E−07 3.13E−08

298.51 3.35E−07 3.35E−07 3.35E−07 3.35E−07 3.35E−07

333.98 1.50E−07 1.50E−07 1.50E−07 2.99E−07 1.50E−07

348.01 1.44E−07 1.44E−07 1.44E−07 2.87E−07 1.44E−07

333.98 2.99E−08 2.99E−08 2.99E−08 2.99E−07 2.99E−08

319.95 1.56E−07 1.56E−07 1.56E−07 3.13E−07 1.56E−07

325.49 NA NA NA NA NA

327.48 NA NA NA NA NA

301.48 3.32E−08 3.32E−08

303.50 3.29E−08 3.29E−08 3.29E−08 3.29E−07 3.29E−07

[0109] NA=not active TABLE 2 Cytotoxicity of Spisulosine Analogs (IC50,Molar) Solid Tumors Line

Bladder 5637 4.72E−08 6.34E−06 3.65E−08 Breast MX-1 1.95E−06 Colon HT-291.28E−07 6.43E−08 9.07E−06 2.64E−07 Gastric Hs746t 3.95E−07 LiverSK-HEP-1 2.97E−07 NSCL A549 8.57E−08 3.43E−08 9.79E−06 1.01E−05 OvarySK-OV-3 7.02E−07 Pancreas PANC-1 1.67E−07 7.22E−07 8.64E−08 Pharynx FADU2.49E−07 1.03E−08 8.12E−08 7.84E−08 Prostate PC-3 8.60E−08 4.9E−083.79E−07 Prostate DU-145 7.39E−08 9.86E−06 2.01E−07 Prostate LNCAP4.44E−08 7.69E−06 7.15E−08 Renal 786-O 1.38E−07 SCL NCI-H187 1.63E−077.17E−06 NA Retinoblastoma Y-79 4.65E−06 NA NA Melanoma Mel-28 7.21E−06NA 1.03E−05 Fibrosarcoma SW 694 NA 6.49E−06 1.04E−05 1.01E−05Chondrosarcoma CHSA 1.80E−08 1.58E−06 9.65E−06 Osteosarcoma OSA-FH1.83E−07 8.60E−06 NA Methodology: MTS. 4-Parameter Curve Fit w/SoftMax.Values are Molar NA = not active Solid Tumors Line

Bladder 5637 7.80E−06 3.26E−06 NA 2.99E−05 Breast MX-1 NA 2.84E−061.49E−05 Colon HT-29 9.11E−06 NA NA Gastric Hs746t NA Liver SK-HEP-1 NANSCL A549 1.03E−05 4.90E−05 NA NA Ovary SK-OV-3 NA Pancreas PANC-11.86E−07 NA NA NA Pharynx FADU 2.25E−07 1.96E−05 NA NA Prostate PC-31.02E−05 Prostate DU-145 7.55E−08 NA Prostate LNCAP 6.35E−06 NA Renal786-O NA 1.62E−07 NA SCL NCI-H187 7.29E−06 3.55E−06 Retinoblastoma Y-799.51E−06 1.21 E−05 Melanoma Mel-28 9.4E−06 NA NA NA Fibrosarcoma SW 6947.57E−06 Chondrosarcoma CHSA 8.94E−06 NA NA NA Osteosarcoma OSA-FH8.52E−06 NA NA 1.49E−05 Solid Tumors Line

Bladder 5637 NA 1.58E−06 1.45E−06 Breast MX-1 NA 1.72E−06 4.29E−06 ColonHT-29 NA NA Gastric Hs746t 1.62E−05 Liver SK-HEP-1 1.55E−05 NSCL A5492.01E−05 NA Ovary SK-OV-3 NA Pancreas PANC-1 NA NA Pharynx FADU 1.43E−052.99E−06 3.96E−06 Prostate PC-3 2.18E−05 Prostate DU-145 4.95E−08Prostate LNCAP NA Renal 786-O NA 5.98E−05 3.30E−06 SCL NCI-H187Retinoblastoma Y-79 1.65E−06 Melanoma Mel-28 NA NA 2.54E−06 FibrosarcomaSW 694 Chondrosarcoma CHSA NA NA 4.62E−06 Osteosarcoma OSA-FH NA NAMethodology: MTS. 4-Parameter Curve Fit w/SoftMax. Values are Molar NA =not active

[0110] TABLE 3 Cytotoxicity of Spisulosine Analogs (IC50, Molar)Leukemias/Lymphomas Line

ALL (Promyelocytic leukemia) HL-60 4.25E−07 ALL (Acute lymphobalstic)Molt 3 1.12E−06 7.61E−06 9.83E−09 CML (Chronic myelogenous) K5627.84E−07 ALL (B-cell) CCRF-SB NA Leukemia (Hairy B-cell) Mo-B Leukemia(Plasma cell) ARH-77 6.82E−07 Lymphoma (T cell) H9 1.55E−06 Lymphoma(Cutaneous T cell) Hut 78 2.16E−06 1.06E−05 NA 8.81E−06 Lymphoma MC1168.82E−06 1.09E−05 9.58E−06 (undifferentiated) Lymphoma (Burkitts B cell)RAMOS 2.14E−06 Lymphoma (Histiocytic) U-937 9.81E−07 2.98E−08 NALymphoma (B cell) CCRF-SB Lymphoma (B cell) MoB Lymphoma (Burkittsascites) P3HR1 3.37E−06 Methodology: MTS. 4-Parameter Curve Fitw/SoftMax. Values are Molar NA = not active Leukemias/Lymphomas Line

ALL (Promyelocytic leukemia) HL-60 ALL (Acute lymphobalstic) Molt 33.76E−08 2.61E−05 NA CML (Chronic myelogenous) K562 0.001 ALL (B-cell)CCRF-SB Leukemia (Hairy B-cell) Mo-B Leukemia (Plasma cell) ARH-77Lymphoma (T cell) H9 NA NA NA Lymphoma Hut 78 9.15E−06 (Cutaneous Tcell) Lymphoma MC116 NA NA NA (undifferentiated) Lymphoma (Burkitts Bcell) RAMOS NA NA Lymphoma U-937 NA NA (Histiocytic) Lymphoma (B cell)CCRF-SB Lymphoma (B cell) MoB Lymphoma (Burkitts P3HR1 ascites)Leukemias/Lymphomas Line

ALL (Promyelocytic leukemia) HL-60 1.29E−06 ALL (Acute lymphobalstic)Molt 3 1.43E−05 5.81E−07 CML (Chronic myelogenous) K562 ALL (B-cell)CCRF-SB Leukemia (Hairy B-cell) Mo-B Leukemia (Plasma cell) ARH-77Lymphoma (T cell) H9 2.59E−06 5.98E−06 Lymphoma (Cutaneous T cell) Hut78 Lymphoma (undifferentiated) MC116 NA NA Lymphoma (Burkitts B cell)RAMOS 1.65E−06 1.21E−06 Lymphoma (Histiocytic) U-937 NA NA Lymphoma (Bcell) CCRF-SB Lymphoma (B cell) MoB Lymphoma (Burkitts ascites) P3HR1Methodology: MTS. 4-Parameter Curve Fit w/SoftMax. Values are Molar NA =not active

[0111] Experimental Section

[0112] General Procedures

[0113] All solvents were reagent grade (used in work-ups) or HPLC grade(used as reaction and/or as purification solvent). Anhydrous solventswere used directly as supplied by the manufacturer. All other reagentswere commercial compounds of the highest purity available. All aminoacids and their derivatives used as starting materials were commerciallyavailable. Compounds 1 and 39 were described in the International PatentWO 99/52521. Analytical thin-layer chromatography (TLC) was performed onMerck silica gel aluminium sheets (60, F254) precoated with afluorescent indicator. Visualization was effected using ultravioletlight (254 nm), phosphomolybdic acid (7% w/v) in 95% ethanol. Proton andcarbon magnetic resonance spectra (¹H, ¹³C-NMR) were recorded on aVarian-300 (300 MHz) Fourier transform spectrometer, and chemical shiftswere expressed in parts per million (ppm) relative to CHCl₃ as aninternal reference (7.26 ppm for ¹H and 77.0 for ¹³C). Multiplicitiesare designated as singlet (s), doublet (d), doublet of doublets (dd),doublet of triplets (dt), triplet (t), quartet (q), quintet (quint),multiplet (m), and broad singlet (br s). Electrospray ionization massspectra (ESI-MS) were obtained on a Hewlett Packard Series 1100 MSD.Flash column chromatography was carried out on E. Merck silica gel 60(240-400 mesh) using the solvent systems listed under individualexperiments.

EXAMPLES OF THE INVENTION

[0114] Illustrative examples of the synthesis of spisulosine derivativesaccording to the present invention are as follows:

EXAMPLE 1

[0115] (S)-2-(N,N-Dibenzylamino)-propionaldehyde, 4.

[0116] To a cold (−78° C.) solution of (COCl)₂ (2M in CH₂Cl₂, 2.47 mL,4.94 mmol) in CH₂Cl₂ (8 mL), DMSO (0.70 mL, 9.89 mmol) was addeddropwise. After stirring at −78° C. for 15 min, a solution of(S)-2-(N,N-dibenzylamino)-1-propanol (1.01 g, 3.96 mmol) in CH₂Cl₂ (10mL) was added dropwise. The mixture was stirred at −78° C. for 1 h, andthen Et₃N (2.76 mL, 19.78 mmol) was added. The reaction was warmed up to0° C. and stirred for 15 min, followed by the addition of NH₄Cl (25 mL,sat. aq.). The crude was extracted with CH₂Cl₂ (3×25 mL), washedsuccessively with NaHCO₃ (50 mL, sat. aq.) and brine (50 mL), dried overNa₂SO₄ and concentrated in vacuo. Aldehyde 4 was obtained as a yellowoil and used without further purification (928 mg, 93% yield).

[0117] R_(f) 0.57 (hexane/EtOAc 5:1);

[0118]¹H NMR (300 MHz, CDCl₃) δ1.18 (d, 3H, J=6.7 Hz), 3.33 (q, 1H,J=6.7 Hz), 3.57 (d, 2H, J=13.8 Hz), 3.74 (d, 2H, J=13.6 Hz), 7.23-7.42(m, 10H), 9.73 (s, 1H);

[0119]¹³C NMR (75 MHz, CDCl₃) δ6.8, 54.9, 62.8, 127.3, 128.4, 128.8,139.0, 204.5.

EXAMPL 2

[0120] (S)-2-(N,N-Dibenzylamino)-1-butan 1, 5.

[0121] To a solution of (S)-2-amino-1-butanol (1.0 mL, 10.58 mmol) inMeOH (20 mL), BnBr (5.0 mL, 42.32 mmol) and K₂CO₃ (5.85 g, 42.32 mmol)were added. The mixture was stirred at 60° C. for 5 h, and then cooleddown to room temperature and filtered, washing the solid with EtOAc. Thefiltrates were concentrated in vacuo and the residue purified by columnchromatography on silica (100% hexane to hexane/EtOAc 5:1) to obtainalcohol 5 as a white solid (2.7 g, 95% yield).

[0122] R_(f) 0.26 (hexane/EtOAc 5:1);

[0123]¹H NMR (300 MHz, CDCl₃) δ0.98 (t, 3H, J=7.5 Hz), 1.25-1.37 (m,1H), 1.79-1.89 (m, 1H), 2.74-2.83 (m, 1H), 3.31 (br s, 1H), 3.45-3.52(m, 1H), 3.50 (d, 2H, J=13.1 Hz), 3.55-3.65 (m, 1H), 3.88 (d, 2H, J=13.3Hz), 7.26-7.41 (m, 10H);

[0124]¹³C NMR (75 MHz, CDCl₃) δ11.6, 17.8, 53.0, 60.4, 127.0, 128.3,128.8, 139.3.

EXAMPLE 3

[0125] (S)-2-(N,N-Dibenzylamino)-butyraldehyde, 6.

[0126] According to the method of Example 1, from alcohol 5 (1.0 g, 3.7mmol), aldehyde 6 was obtained as a yellow oil and used without furtherpurification (1.0 g, 100% yield).

[0127] R_(f) 0.73 (hexane/Et₂O 1:1);

[0128]¹H NMR (300 MHz, CDCl₃) δ0.97 (t, 3H, J=7.5 Hz), 1.64-1.85 (m,2H), 3.08 (t, 1H, J=6.8 Hz), 3.72 (d, 2H, J=13.6 Hz), 3.80 (d, 2H,J=13.8 Hz), 7.22-7.39 (m, 10H), 9.73 (s, 1H).

EXAMPLE 4

[0129] (S)-2-(N-Benzyloxycarbonylamino)-1-butanol, 7.

[0130] To a cold (0° C.) solution of (S)-2-amino-1-butanol (2.0 g, 22.5mmol) in acetone/H₂O 1:1 (50 mL), Na₂CO₃ (8.7 g, 81.9 mmol) and BnOCOCl(5.8 g, 33.8 mmol) were added. After stirring at 0° C. for 1 h, thesolid was filtered off and washed with acetone (2×30 mL). The filtrateswere concentrated in vacuo and the residue was purified by columnchromatography on silica (100% CH₂Cl₂ to CH₂Cl₂/MeOH 20:1) to obtainalcohol 7 as a white solid (2.14 g, 43% yield).

EXAMPLE 5

[0131] (S)-2-(N-Benzyloxycarbonylamino)-butyraldehyde, 8.

[0132] According to the method of Example 1, from alcohol 7 (750 mg, 3.4mmol), aldehyde 8 was obtained as a yellow oil and used without furtherpurification (700 mg, 94% yield).

[0133] R_(f) 0.31 (MeOH/CH₂Cl₂ 3:1).

EXAMPLE 6

[0134] Benzyl (S)-2-(N,N-dibenzylamino)-pentanoate, 9.

[0135] To a solution of L-norvaline (685 mg, 5.85 mmol) in MeCN (15 mL),BnBr (3.48 mL, 29.24 mmol) and K₂CO₃ (4.04 g, 29.24 mmol) were added.The mixture was stirred at 60° C. for 9 h, and then cooled down to roomtemperature and filtered, washing the solid with EtOAc. The filtrateswere concentrated in vacuo and the residue purified by columnchromatography on silica (100% hexane to hexane/EtOAc 5:1) to obtainbenzyl ester 9 as a colorless oil (1.6 g, 71% yield).

[0136] R_(f) 0.29 (hexane/EtOAc 5:1);

[0137]¹H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H, J=7.4 Hz), 1.25-1.40 (m,1H), 1.45-1.60 (m, 1H), 1.70-1.85 (m, 2H), 3.42 (dd, 1H, J=8.2, 6.7 Hz),3.55 (d, 2H, J=13.9 Hz), 3.96 (d, 2H, J=13.9 Hz), 5.18 (d, 1H, J=12.3Hz), 5.30 (d, 1H, J=12.3 Hz), 7.25-7.45 (m, 15H);

[0138]¹³C NMR (75 MHz, CDCl₃) δ13.7, 19.3, 31.6, 54.4, 60.5, 65.8,126.8, 128.1, 128.2, 128.4, 128.5, 128.8, 136.1, 139.7, 173.0.

EXAMPLE 7

[0139] (S)-2-(N,N-Dibenzylamino)-1-pentanol, 10.

[0140] To a cold (0° C.) suspension of LiAlH₄ (184 mg, 4.84 mmol) in THF(10 mL), a solution of ester 9 (375 mg, 0.97 mmol) in THF (2.5 mL) wasadded. The mixture was stirred at 0° C. for 2 h, and then quenched bydropwise addition of EtOH (3 ml′). Na—K tartrate solution (10% aq, 30mL) was added, and the crude was extracted with EtOAc (3×30 mL), driedover Na₂SO₄, concentrated in vacuo and purified by column chromatographyon silica (hexane/EtOAc 5:1) to obtain alcohol 10 as a colorless oil(170 mg, 62% yield).

[0141] R_(f) 0.31 (hexane/EtOAc 5: 1);

[0142]¹H NMR (300 MHz, CDCl₃) δ0.97 (t, 3H, J=7.1 Hz), 1.17-1.42 (m,3H), 1.71-1.76 (m, 1H), 2.80-2.86 (m, 1H), 3.25 (br s, 1H), 3.41-3.56(m, 2H), 3.44 (d, 2H, J=13.3 Hz), 3.85 (d, 2H, J=13.3 Hz), 7.24-7.37 (m,10H);

[0143]¹³C NMR (75 MHz, CDCl₃) δ14.3, 20.3, 27.2, 53.1, 58.7, 60.8,127.1, 128.4, 129.0, 139.3.

EXAMPLE 8

[0144] (S)-2-(N,N-Dibenzylamino)-pentanal, 11.

[0145] According to the method of Example 1, from alcohol 10 (163 mg,0.58 mmol), aldehyde 11 was obtained as a yellow oil and used withoutfurther purification (140 g,. 87% yield).

[0146] R_(f) 0.73 (hexane/EtOAc 10:1);

[0147]¹H NMR (300 MHz, CDCl₃) δ0.89 (t, 3H, J=7.3 Hz), 1.34-1.44 (m,2H), 1.60-1.76 (m, 2H), 3.17 (t, 1H, J=6.7 Hz), 3.73 (d, 2H, J=13.8 Hz),3.81 (d, 2H, J=13.8 Hz), 7.23-7.40 (m, 10H), 9.74 (s, 1H).

EXAMPLE 9

[0148] Benzyl (S)-2-(N,N-dibenzylamino)-3-methylbutyrate, 12.

[0149] According to the method of Example 6, from L-valine (927 mg, 7.91mmol), benzyl ester 12 was obtained as a colorless oil (2.58 g, 84%yield).

[0150] R_(f) 0.31 (hexane/EtOAc 10:1);

[0151]¹H NMR (300 MHz, CDCl₃) δ0.86 (d, 3H, J=6.4 Hz), 1.11 (d, 3H,J=6.5 Hz), 2.20-2.35 (m, 1H), 3.02 (d, 1H, J=10.7 Hz), 3.39 (d, 2H,J=13.9 Hz), 4.07 (d, 2H, J=13.9 Hz), 5.25 (d, 1H, J=12.3 Hz), 5.39 (d,1H, J=12.1 Hz), 7.27-7.54 (m, 15H);

[0152]¹³C NMR (75 MHz, CDCl₃) δ19.5, 19.9, 27.2, 54.5, 65.6, 68.0,126.9, 128.2, 128.3, 128.5, 128.6, 128.7, 136.1, 139.4, 171.8;

[0153] ESMS calcd for C₂₆H₃₀NO₂ (M+H) 388.2, found 388.2.

EXAMPLE 10

[0154] (S)-2-(N,N-Dibenzylamino)-3-methyl-1-butanol, 13.

[0155] According to the method of Example 7, from ester 12 (2.3 g, 5.93mmol), alcohol 13 was obtained as a colorless oil (1.55 g, 92% yield).

[0156] R_(f) 0.24 (hexane/EtOAc 10:1);

[0157]¹H NMR (300 MHz, CDCl₃) δ0.97 (dd, 3H, J=6.5, 1.2 Hz), 1.17 (dd,3H, J=6.7, 1.2 Hz), 2.05-2.12 (m, 1H), 2.52-2.60 (m, 1H), 3.05 (br s,1H), 3.47 (td, 1H, J=10.2, 1.3 Hz), 3.61 (br d, 1H, J=10.1 Hz), 3.71 (d,2H, J=13.3 Hz), 3.91 (d, 2H, J=13.3 Hz), 7.23-7.36 (m, 10H);

[0158]¹³C NMR (75 MHz, CDCl₃) δ20.1, 22.6, 27.5, 54.1, 59.1, 64.6,127.1, 128.4, 129.1, 139.6;

[0159] ESMS calcd for C₁₉H₂₆NO (M+H) 284.2, found 284.2.

EXAMPLE 11

[0160] (S)-2-(N,N-Dibenzylamino)-3-methylbutyraldehyde, 14.

[0161] According to the method of Example 1, from alcohol 13 (450 mg,1.59 mmol), aldehyde 14 was obtained as a yellow oil and used withoutfurther purification (447 mg, 100% yield).

[0162] R_(f) 0.57 (hexane/EtOAc 5:1);

[0163]¹H NMR (300 MHz, CDCl₃) δ0.87 (d, 3H, J=6.5 Hz), 1.08 (d, 3H,J=6.5 Hz), 2.25-2.32 (m, 1H), 2.72 (dd, 1H, J=10.2, 3.7 Hz), 3.70 (d,2H, J=13.6 Hz), 4.02 (d, 2H, J=13.8 Hz), 7.24-7.38 (m, 10H), 9.85 (d,1H, J=3.5 Hz).

EXAMPLE 12

[0164] Benzyl (2S,3S)-2-(N,N-dibenzylamino)-3-methylpentanoate, 15.

[0165] According to the method of Example 6, from L-isoleucine (1.0 g,7.6 mmol), benzyl ester 15 was obtained as a colorless oil (2.4 g, 80%yield).

[0166] R_(f) 0.62 (hexane/EtOAc 20:1);

[0167]¹H NMR (300 MHz, CDCl₃) δ0.71-0.79 (m, 6H), 1.09-1.21 (m, 1H),1.82-2.01 (m, 2H), 3.02 (d, 1H, J=6.5 Hz), 3.23 (d, 2H, J=9.5 Hz), 3.89(d, 2H, J=9.5 Hz), 5.15 (d, 1H, J=7.5 Hz), 5.24 (d, 1H, J=7.5 Hz),7.11-7.46 (m, 15H);

[0168] ESMS calcd for C₂₇H₃₂NO₂ (M+H) 402.2, found 402.5.

EXAMPLE 13

[0169] (2S,3S)-2-(N,N-Dibenzylamino)-3-methyl-1-pentanol, 16.

[0170] According to the method of Example 7, from ester 15 (0.50 g, 1.23mmol), alcohol 16 was obtained as a colorless oil (0.36 g, 99% yield).

[0171] R_(f) 0.43 (hexane/EtOAc 9:1);

[0172]¹H NMR (300 MHz, CDCl₃) δ0.92-0.99 (m, 6H), 1.13-1.18 (m, 1H),1.63-1.67 (m, 1H), 1.88-1.97 (m, 1H), 2.63-2.67 (m, 1H), 3.45 (d, 2H,J=6.5 Hz), 3.49 (d, 2H, J=9.5 Hz), 3.88 (d, 2H, J=9.5 Hz), 7.18-7.42 (m,10H);

[0173]¹³C NMR (75 MHz, CDCl₃) δ11.4, 15.8, 28.2, 32.7, 53.9, 58.7, 62.7,127.0, 128.3, 129.0, 139.7;

[0174] ESMS calcd for C₂₀H₂₈NO (M+H) 298.4, found 298.4.

EXAMPLE 14

[0175] (2S,3S)-2-(N,N-Dibenzylamino)-3-methylpentanal, 17.

[0176] According to the method of Example 1, from alcohol 16 (479 mg,1.61 mmol), aldehyde 17 was obtained as a yellow oil and used withoutfurther purification (470 mg, 98% yield).

[0177] R_(f) 0.71 (hexane/EtOAc 9:1);

[0178]¹H NMR (300 MHz, CD₃OD) δ0.78-0.82 (m, 6H), 1.13-1.20 (m, 1H),1.80-1.85 (m, 1H), 2.02-2.10 (m, 1H), 2.71 (dd, 1H, J=7.8, 3.5 Hz), 3.61(d, 2H, J=11.8 Hz), 3.99 (d, 2H, J=11.8 Hz), 7.15-7.29 (m, 10H), 9.77(d, 1H, J=2.0 Hz).

EXAMPLE 15

[0179] Benzyl(S)-3-(4′-benzyloxyphenyl)-2-(N,N-dibenzylamino)-propionate, 18.

[0180] According to the method of Example 6, from L-tyrosine (1.49 g,8.22 mmol), ester 18 was obtained as a colorless oil (2.10 g, 47%yield).

[0181] R_(f) 0.25 (hexane/EtOAc 10:1);

[0182]¹H NMR (300 MHz, CDCl₃) δ3.06 (dd, 1H, J=14.0, 8.1 Hz), 3.20 (dd,1H, J=14.0, 7.6 Hz), 3.65 (d, 2H, J=13.9 Hz), 3.79 (t, 1H, J=7.7 Hz),4.04 (d, 2H, J=13.9 Hz), 5.15 (s, 2H), 5.22 (d, 1H, J=12.2 Hz), 5.33 (d,1H, J=12.2 Hz), 6.94 (d, 2H, J=8.8 Hz), 7.03 (d, 2H, J=8.5 Hz),7.26-7.57 (m, 20H);

[0183]¹³C NMR (75 MHz, CDCl₃) δ34.7, 54.3, 62.5, 65.9, 69.9, 102.1,114.5, 126.8, 127.4, 127.8, 128.1, 128.2, 128.4, 128.5, 128.5, 128.6,130.3, 135.9, 137.1, 139.2, 157.3, 172.1;

[0184] ESMS calcd for C₃₇H₃₆NO₃ (M+H) 542.3, found 542.3.

EXAMPLE 16

[0185] (S)-3-(4′-Benzyloxyphenyl)-2-(N,N-dibenzylamino)-1-propanol, 19.

[0186] According to the method of Example 7, from ester 18 (1.90 g, 3.51mmol), alcohol 19 was obtained as a colorless oil (1.20 g, 78% yield).

[0187] R_(f) 0.15 (hexane/EtOAc 5:1);

[0188]¹H NMR (300 MHz, CDCl₃) δ2.45 (dd, 1H, J=14.6, 10.7 Hz), 3.05-3.15(m, 3H), 3.44 (br s, 1H), 3.52-3.60 (m, 1H), 3.55 (d, 2H, J=13.3 Hz),3.98 (d, 2H, J=13.3 Hz), 5.10 (s, 2H), 6.97 (d, 2H, J=8.6 Hz), 7.08 (d,2H, J=8.4 Hz), 7.29-7.52 (m, 15H);

[0189]¹³C NMR (75 MHz, CDCl₃) δ30.8, 53.1, 60.3, 60.8, 69.9, 114.9,127.2, 127.3, 127.8, 128.4, 128.5, 128.9, 129.8, 131.3, 137.0, 139.1,157.2;

[0190] ESMS calcd for C₃₀H₃₂NO₂ (M+H) 438.2, found 438.3.

EXAMPLE 17

[0191] (S)-2-(N,N-dibenzylamino)-3-(4′-benzyloxyphenyl)-propionaldehyde,20.

[0192] According to the method of Example 1, from alcohol 19 (600 mg,1.37 mmol), aldehyde 20 was obtained as a yellow oil and used withoutfurther purification (597 mg, 100% yield).

[0193] R_(f) 0.38 (hexane/EtOAc 5:1);

[0194]¹H NMR (300 MHz, CDCl₃) δ2.89 (dd, 1H, J=14.1, 6.1 Hz), 3.09 (dd,1H, J=14.1, 7.2 Hz), 3.51 (t, 1H, J=6.8 Hz), 3.67 (d, 2H, J=13.8 Hz),3.82 (d, 2H, J=13.8 Hz), 5.06 (s, 2H), 6.88 (d, 2H, J=8.7 Hz), 7.06 (d,2H, J=8.6 Hz), 7.22-7.45 (m, 15H), 9.72 (s, 1H).

EXAMPLE 18

[0195] Methyl (S)-2,5-bis-(N,N-dibenzylamin)-pentanoate, 21.

[0196] According to the method of Example 6, from L-ornitine methylester (1.20 g, 5.48 mmol), ester 21 was obtained as a colorless oil(2.18 g, 79% yield).

[0197] R_(f) 0.27 (hexane/EtOAc 5:1);

[0198]¹H NMR (300 MHz, CDCl₃) δ1.50-1.60 (m, 1H), 1.75-1.90 (m, 3H),2.41 (t, 2H, J=6.7 Hz), 3.36 (t, 1H, J=7.3 Hz), 3.55 (d, 2H, J=13.8 Hz),3.63 (d, 2H, J=13.9 Hz), 3.65 (d, 2H, J=13.6 Hz), 3.84 (s, 3H), 4.02 (d,2H, J=13.8 Hz), 7.29-7.45 (m, 20H);

[0199]¹³C NMR (75 MHz, CDCl₃) δ23.6, 27.2, 50.8, 52.9, 54.5, 58.2, 60.6,126.7, 126.9, 128.0, 128.1, 128.7, 128.8, 139.6, 139.7, 173.4;

[0200] ESMS calcd for C₃₄H₃₉N₂O₂ (M+H) 507.3, found 507.3.

EXAMPLE 19

[0201] (S)-2,5-Bis-(N,N-dibenzylamino)-1-pentanol, 22.

[0202] According to the method of Example 7, from ester 21 (1.75 g, 3.45mmol), alcohol 22 was obtained as a colorless oil (1.50 g, 91% yield).

[0203] R_(f) 0.27 (hexane/EtOAc 5:1);

[0204]¹H NMR (300 MHz, CDCl₃) δ1.25-1.35 (m, 1H), 1.53-1.63 (m, 2H),1.78-1.89 (m, 1H), 2.60 (t, 2H, J=6.8 Hz), 2.83-2.93 (m, 1H), 3.35 (brs, 1H), 3.53 (d, 2H, J=13.3 Hz), 3.54-3.64 (m, 2H), 3.70 (d, 2H, J=13.6Hz), 3.76 (d, 2H, J=13.8 Hz), 3.93 (d, 2H, J=13.3 Hz), 7.36-7.59 (m,20H);

[0205]¹³C NMR (75 MHz, CDCl₃) δ22.7, 24.6, 53.0, 53.6, 58.4, 58.9, 60.7,126.7, 127.0, 128.0, 128.2, 128.6, 128.8, 139.2, 139.6;

[0206] ESMS calcd for C₃₃H₃₉N₂O (M+H) 479.3, found 479.3.

EXAMPLE 20

[0207] (S)-2,5-Bis-(N,N-dibenzylamino)-pentanal, 23.

[0208] According to the method of Example 1, from alcohol 22 (505 mg,1.05 mmol), aldehyde 23 was obtained as a yellow oil and used withoutfurther purification (503 mg, 100% yield).

[0209] R_(f) 0.57 (hexane/EtOAc 5:1);

[0210]¹H NMR (300 MHz, CDCl₃) δ1.30-1.40 (m, 1H), 1.55-1.70 (m, 2H),1.75-1.85 (m, 1H), 2.35-2.45 (m, 2H), 3.02-3.08 (m, 1H), 3.52 (d, 2H,J=13.6 Hz), 3.62 (d, 2H, J=13.6 Hz), 3.71 (d, 2H, J=13.8 Hz), 3.81 (d,2H, J=13.8 Hz), 7.28-7.41 (m, 20H), 9.69 (s, 1H).

EXAMPLE 21

[0211] Methyl (R)-2-(N,N-dibenzylamino)-propionate, 24.

[0212] According to the method of Example 6, from D-alanine methyl ester(536 mg, 3.84 mmol), ester 24 was obtained as a colorless oil (625 mg,57% yield).

[0213] R_(f) 0.40 (hexane/EtOAc 10:1);

[0214]¹H NMR (300 MHz, CDCl₃) δ1.35 (d, 3H, J=7.1 Hz), 3.53 (q, 1H,J=7.0 Hz), 3.65 (d, 2H, J=13.8 Hz), 3.75 (s, 3H), 3.85 (d, 2H, J=13.8Hz), 7.22-7.42 (m, 10H).

EXAMPLE 22

[0215] (R)-24N,N-dibenzylamino)-1-propanol, 25.

[0216] According to the method of Example 7, from ester 24 (625 mg, 2.20mmol), alcohol 25 was obtained as a colorless oil (450 mg, 80% yield).

[0217] R_(f) 0.21 (hexane/EtOAc 5:1);

[0218]¹H NMR (300 MHz, CDCl₃) δ0.98 (d, 3H, J=7.1 Hz), 2.95-3.05 (m,1H), 3.13 (br s, 1H), 3.35 (d, 2H, J=13.8 Hz), 3.40-3.55 (m, 2H), 3.81(d, 2H, J=13.8 Hz), 7.19-7.41 (m, 10H).

EXAMPLE 23

[0219] (R)-2-(I,N-Dibenzylamino)-propionaldehyde, 26.

[0220] According to the method of Example 1, from alcohol 25 (475 mg,1.86 mmol), aldehyde 26 was obtained as a yellow oil and used withoutfarther purification (445 mg, 94% yield).

[0221] R_(f) 0.5⁷ (hexane/EtOAc 5:1);

[0222]¹H NMR (300 MHz, CDCl₃) δ1.18 (t, 3H, J=6.7 Hz), 3.33 (q, 1H,J=6.7 Hz), 3.57 (d, 2H, J=13.8 Hz), 3.74 (d, 2H, J=13.6 Hz), 7.23-7.42(m, 10H), 9.73 (s, 1H).

EXAMPLE 24

[0223] (S)-241%Benzyloxycarbonylamino)-1-propanol, 27.

[0224] To a cold (−15° C.) solution of N-Cbz-L-alanine (1.0 g, 4.5 mmol)in THF (15 mL), Et₃N (360 mg, 4.5 mmol) and i-BuOCOCl (610 mg, 4.5 mmol)were added. After stirring at room temperature for 20 min, the solidEt₃N.HCl was filtered off and washed with THF. The filtrates were cooledto −15° C. and a solution of NaBH₄ (260 mg, 6.75 mmol) in H₂O (10 mL)was added. After 1 h, the reaction was quenched with H₂O (70 mL) and theTHF removed in vacuo. The residue was extracted with EtOAc (3×30 mL),washed with brine (100 mL), dried over MgSO₄ and concentrated in vacuoto obtain alcohol 27 as a white solid (780 mg, 82% yield).

[0225]¹H NMR (500 MHz, CDCl₃) δ1.15 (d, 3H, J=6.8 Hz), 2.75-2.80 (m,2H), 3.45-3.55 (m, 1H), 3.60-3.65 (m, 1H), 3.80-3.85 (m, 1H), 5.09 (s,2H), 7.30-7.35 (m, 5H).

EXAMPLE 25

[0226] (S)-2-(N-Benzyloxycarbonylamino)-propionaldehyde, 28.

[0227] According to the method of Example 1, from alcohol 27 (750 mg,3.6 mmol), aldehyde 28 was obtained as a yellow oil and used withoutfurther purification (680 mg, 92% yield).

[0228] R_(f) 0.31 (MeOH/CH₂Cl₂ 3:1).

EXAMPLE 26

[0229] (2S,3R)-2-(N,N-Dibenzylamino)-3-tetradecanol, 29.

[0230] To a suspension of Mg (155 mg, 6.38 mmol) and a few crystals ofI₂ in THF (3.1 mL), an aliquot of 1-bromoundecane (0.25 mL, 1.12 mmol)was added and the mixture was stirred at 60° C. until the red color ofthe solution disappeared. Then the remainder of 1-bromoundecane (0.46mL, 2.07 mmol) was added and the reaction was stirred at roomtemperature for 1 h. The Grignard solution formed thereof was cooleddown to 0° C. and a solution of aldehyde 4 (323.5 mg, 1.28 mmol) in THF(1.6 mL) was added via cannula. After stirring overnight at roomtemperature, the reaction was quenched with HCl (3N, 10 mL) extractedwith EtOAc (3×10 mL), washed successively with NaHCO₃ (20 mL, sat. aq.)and brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo. Thecrude was purified by column chromatography on silica (100% hexane to10:1 hexane/EtOAc) to obtain a mixture of diastereoisomers. Furtherpurification by HPLC on silica (95:5 to 80:20 hexane/MTBE) afforded pureanti alcohol 29 as a colorless oil (205 mg, 39% yield).

[0231] R_(f) 0.50 (hexane/EtOAc 5:1);

[0232]¹H NMR (300 MHz, CDCl₃) δ0.92 (t, 3H, J=6.9 Hz), 1.13 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 18H), 1.65-1.80 (m, 2H), 1.87 (br s, 1H), 2.74(quint, 1H, J=6.7 Hz), 3.49 (d, 2H, J=13.9 Hz), 3.57-3.65 (m, 1H), 3.79(d, 2H, J=13.8 Hz), 7.22-7.38 (m, 10H);

[0233]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.6, 29.6,29.7, 31.9, 34.3, 54.8, 57.3, 73.7, 126.9, 128.2, 128.8, 140.2;

[0234] ESMS calcd for C₂₈H₄₄NO (M+H) 410.3, found 410.6.

EXAMPLE 27

[0235] (2S,3R)-2-Amino-3-tetradecanol, 30.

[0236] To a solution of N,N-dibenzylamine 29 (182 mg, 0.44 mmol) in MeOH(4.5 mL) at room temperature, Pd(OH)₂—C (20% wt, 24 mg, 0.04 mmol) wasadded. The mixture was purged with a stream of dry Ar, and then H₂. Thereaction was stirred overnight under a H₂ atmosphere (1 atm). Thecatalyst was filtered off through a 0.45 μm teflon filter inpolypropylene housing, washing the filter with MeOH (30 mL) and thesolvent was evaporated in vacuo. The crude was purified by columnchromatography on silica (90:10 CH₂Cl₂/MeOH to 100% MeOH) to obtainaminoalcohol 30 as a white solid (87 mg, 85% yield).

[0237]¹H NMR (300 MHz, CDCl₃) □0.87 (t, 3H, J=6.7 Hz), 1.03 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 18H), 1.45-1.55 (m, 2H), 2.66 (br s, 3H),2.95-3.05 (m, 1H), 3.45-3.55 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ14.1,16.2, 22.7, 26.2, 29.3, 29.6, 29.8, 31.9, 32.5, 50.5, 74.2;

[0238] ESMS calcd for C₁₄H₃₂NO (M+H) 230.2, found 230.4.

EXAMPLE 28

[0239] (2S,3R)-2-(N,N-Dibenzylamino)-3-pentadecanol, 31.

[0240] According to the method of Example 26, from aldehyde 4 (273 mg,1.08 mmol) and 1-bromododecane (671 mg, 2.69 mmol), alcohol 31 wasobtained as a colorless oil (195 mg, 43% yield).

[0241] R_(f) 0.50 (hexane/EtOAc 5:1);

[0242]¹H NMR (300 MHz, CDCl₃) δ0.90 (t, 3H, J=6.9 Hz), 1.12 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 20H), 1.65-1.75 (m, 2H), 1.82 (br s, 1H), 2.73(quint, 1H, J=6.7 Hz), 3.48 (d, 2H, J=13.8 Hz), 3.57-3.65 (m, 1H), 3.78(d, 2H, J=13.8 Hz), 7.21-7.37 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ8.6,14.1, 22.7, 25.9, 29.3, 29.6, 29.6, 29.7, 31.9, 34.3, 54.8, 57.3, 73.7,126.9, 128.2, 128.8, 140.2;

[0243] ESMS calcd for C₂₉H₄₆NO (M+H) 424.4, found 424.7.

EXAMPLE 29

[0244] (2S,3R)-2-Amino-3-pentadecanol, 32.

[0245] According to the method of Example 27, from N,N-dibenzylamine 31(145 mg, 0.34 mmol), aminoalcohol 32 was obtained as a white solid (65mg, 78% yield).

[0246]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.9 Hz), 1.02 (d, 3H,J=6.4 Hz), 1.20-1.40 (m, 20H), 1.45-1.55 (m, 2H), 2.38 (br s, 3H),2.93-3.03 (m, 1H), 3.42-3.52 (m, 1H);

[0247]¹³C NMR (75 MHz, CDCl₃) δ14.1, 16.4, 22.7, 26.2, 29.3, 29.6, 29.8,31.9, 32.5, 50.5, 74.4;

[0248] ESMS calcd for C₁₅H₃₄NO (M+H) 244.3, found 244.4.

EXAMPLE 30

[0249] (2S,3R)-2-(N,N-Dibenzylamino)-3-hexadecanol, 33.

[0250] According to the method of Example 26, from aldehyde 4 (332 mg,1.31 mmol) and 1-bromotridecane (863 mg, 3.28 mmol), alcohol 33 wasobtained as a colorless oil (172 mg, 30% yield).

[0251] R_(f) 0.50 (hexane/EtOAc 5:1);

[0252]¹H NMR (300 MHz, CDCl₃) δ0.90 (t, 3H, J=6.9 Hz), 1.12 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 22H), 1.65-1.75 (m, 2H), 1.84 (br s, 1H), 2.73(quint, 1H, J=6.5 Hz), 3.49 (d, 2H, J=13.8 Hz), 3.57-3.65 (m, 1H), 3.78(d, 2H, J=13.8 Hz), 7.23-7.38 (m, 10H);

[0253]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.6, 29.7,31.9, 34.3, 54.8, 57.3, 73.6, 126.8, 128.2, 128.7, 140.2;

[0254] ESMS calcd for C₃₀H₄₈NO (M+H) 438.4, found 438.7.

EXAMPLE 31

[0255] (2S,3R)-2-Amino-3-hexadecanol, 34.

[0256] According to the method of Example 27, from N,N-dibenzylamine 33(149 mg, 0.34 mmol), aminoalcohol 34 was obtained as a white solid (62mg, 71% yield).

[0257]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=7.0 Hz), 1.05 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 22H), 1.45-1.55 (m, 2H), 2.95-3.10 (m, 4H),3.48-3.58 (m, 1H);

[0258]¹³C NMR (75 MHz, CDCl₃) δ14.1, 15.9, 22.7, 26.2, 29.3, 29.6, 29.7,29.7, 31.9, 32.6, 50.6, 73.9;

[0259] ESMS calcd for C₁₆H₃₆NO (M+H) 258.3, found 258.5.

EXAMPLE 32

[0260] (2S,3R)-2-Amin-3-hexadecanol hydrochloride, 35.

[0261] To a solution of amine 34 (26 mg, 0.10 mmol) in dioxane (0.5 mL),anhydrous HCl solution in dioxane (5.3M, 0.38 mL, 2.02 mmol) was added.After stirring at room temperature for 5 h, the solvent was removed invacuo. The resulting solid was washed with dioxane to obtainhydrochloride 35 as a white solid (19 mg, 64% yield).

[0262]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.7 Hz), 1.21 (d, 3H,J=6.7 Hz), 1.25-1.40 (m, 22H), 1.45-1.60 (m, 2H), 3.27 (qd, 1H, J=6.7,3.0 Hz), 3.65-3.73 (m, 1H);

[0263]¹³C NMR (75 MHz, CD₃OD) δ12.1, 14.4, 23.7, 27.0, 30.5, 30.6, 30.7,30.7, 30.8, 33.1, 34.0, 52.6, 71.6;

[0264] ESMS calcd for C₁₆H₃₆NO (M−Cl) 258.3, found 258.4.

EXAMPLE 33

[0265] (2S,3R)-2-(N,N-Dibenzylamino)-3-heptadecanol, 36.

[0266] According to the method of Example 26, from aldehyde 4 (309 mg,1.21 mmol) and 1-bromotetradecane (1.34 g, 4.84 mmol), alcohol 36 wasobtained as a colorless oil (270 mg, 49% yield).

[0267] R_(f) 50 (hexane/EtOAc 5:1);

[0268]¹H NMR (300 MHz, CDCl₃) δ0.91 (t, 3H, V 6.9 Hz), 1.12 (d, 3H,J=6.7 Hz), 1.20-1.40 (m, 24H), 1.65-1.75 (m, 2H), 1.85 (br s, 1H), 2.73(quint, 1H, J=7 6.4 Hz), 3.49 (d, 2H, J=13.9 Hz), 3.57-3.65 (m, 1H),3.78 (d, 2H, J=13.8 Hz), 7.21-7.38 (m, 10H);

[0269]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.6, 29.7,31.9, 34.4, 54.8, 57.3, 73.6, 126.9, 128.2, 128.8, 140.2;

[0270] ESMS calcd for C₃₁H₅₀NO (M+H) 452.4, found 452.5.

EXAMPLE 34

[0271] (2S,3R)-2-Amino-3-heptadecanol, 37.

[0272] According to the method of Example 27, from N,N-dibenzylamine 36(182 mg, 0.40 mmol), aminoalcohol 37 was obtained as a white solid (81mg, 74% yield).

[0273]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=7.0 Hz), 1.02 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 24H), 1.45-1.55 (m, 2H), 1.85 (br s, 3H),2.94-3.04 (m, 1H), 3.42-3.52 (m, 1H);

[0274]¹³C NMR (75 MHz, CDCl₃) δ14.1, 16.3, 22.7, 26.2, 29.3, 29.7, 31.9,32.5, 50.4, 74.2;

[0275] ESMS calcd for C₁₇H₃₈NO (M+H) 272.3, found 272.3.

EXAMPLE 35

[0276] (2S,3R)-2-Amino-3-heptadecanol hydrochloride, 38.

[0277] According to the method of Example 32, from aminoalcohol 37 (50mg, 0.18 mmol), hydrochloride 38 was obtained as a white solid (41 mg,73% yield).

[0278]¹H NMR (300 MHz, CD₃OD) δ0.80 (t, 3H, J=6.8 Hz), 1.22 (d, 3H,J=6.8 Hz), 1.21-1.40 (m, 24H), 1.41-1.51 (m, 2H), 3.22-3.31 (m, 1H),3.63-3.74 (m, 1H).

EXAMPLE 36

[0279] Bis-((2S,3R)-2-ammonium-3-octadecanol) L-tartrate, 40.

[0280] To a solution of aminoalcohol 1 (63 mg, 0.221 mmol) in MeOH (1.1mL) at room temperature, L-tartaric acid (66 mg, 0.442 mmol) was added.After stirring for 16 h, the solvent was evaporated in vacuo. Theresulting solid was washed with H₂O and dried under vacuum for 8 h toobtain tartrate 40 as a white solid (53 mg, 67% yield).

[0281]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.7 Hz), 1.21 (d, 3H,J=6.7 Hz), 1.25-1.40 (m, 26H), 1.40-1.55 (m, 2H), 3.26 (qd, 1H, J=6.7,3.0 Hz), 3.62-3.72 (m, 1H), 4.43 (d, 2H, J=1.8 Hz);

[0282]¹³C NMR (75 MHz, CD₃OD) δ12.0, 14.4, 23.7, 27.0, 30.5, 30.8, 33.1,34.0, 52.6, 71.7, 73.9;

[0283] ESMS calc for C₁₈H₄₀NO (M=CHOHCO₂) 286.3, found 286.2.

EXAMPLE 37

[0284] (2S,3R)-2-Amino-3-octadecanol hydrochloride, 41.

[0285] According to the method of Example 32, from aminoalcohol 1 (52.5mg, 0.184 mmol), hydrochloride 41 was obtained as a white solid (52 mg,88% yield).

[0286]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.7 Hz), 1.21 (d, 3H,J=6.7 Hz), 1.25-1.40 (m, 26H), 1.40-1.55 (m, 2H), 3.26 (qd, 1H, J=6.7,3.0 Hz), 3.62-3.72 (m, 1H);

[0287]¹³C NMR (75 MHz, CD₃OD) δ12.1, 14.5, 23.7, 27.0, 30.5, 30.7, 30.7,30.8, 33.1, 34.0, 52.6, 71.6;

[0288] ESMS calcd for C₁₈H₄₀NO (M−Cl) 286.3, found 286.2.

EXAMPLE 38

[0289] (2S,3R)-2-(N,N-Dibenzylamino)-3-nonadecanol, 42.

[0290] According to the method of Example 26, from aldehyde 4 (294 mg,1.16 mmol) and 1-bromohexadecane (1.42 g, 4.64 mmol), alcohol 42 wasobtained as a colorless oil (283 mg, 51% yield).

[0291] R_(f) 0.50 (hexane/EtOAc 5:1);

[0292]¹H NMR (300 MHz, CDCl₃) δ0.93 (t, 3H, J=6.9 Hz), 1.14 (d, 3H,J=6.7 Hz), 1.20-1.40 (m, 28H), 1.65-1.80 (m, 2H), 1.95 (br s, 1H), 2.75(quint, 1H, J=6.5 Hz), 3.50 (d, 2H, J=13.8 Hz), 3.57-3.65 (m, 1H), 3.80(d, 2H, J=13.8 Hz), 7.23-7.40 (m, 10H);

[0293]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.6, 29.7,31.9, 34.3, 54.7, 57.2, 73.6, 126.8, 128.2, 128.7, 140.1;

[0294] ESMS calcd for C₃₃H₅₄NO (M+H) 480.4, found 480.5.

EXAMPLE 39

[0295] (2S,3R)-2-Amino-3-nonadecanol, 2.

[0296] According to the method of Example 27, from N,N-dibenzylamine 42(204 mg, 0.43 mmol), aminoalcohol 2 was obtained as a white solid (91mg, 72% yield).

[0297]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=6.9 Hz), 1.01 (d, 3H,J=6.4 Hz), 1.20-1.40 (m, 28H), 1.45-1.55 (m, 2H), 1.77 (br s, 3H),2.92-3.02 (m, 1H), 3.39-3.49 (m, 1H);

[0298]¹³C NMR (75 MHz, CDCl₃) δ14.1, 16.7, 22.7, 26.2, 29.3, 29.6, 29.7,29.8, 31.9, 32.4, 50.3, 74.6;

[0299] ESMS calcd for C₁₉H₄₂NO (M+H) 300.3, found 300.3.

EXAMPLE 40

[0300] (2S,3R)-2-Amino-3-nonadecanol hydrochloride, 43.

[0301] According to the method of Example 32, from aminoalcohol 2 (530mg, 1.70 mmol), hydrochloride 43 was obtained as a white solid (454 mg,76% yield).

[0302]¹H NMR (300 MHz, CD₃OD) δ0.86 (t, 3H, J=6.8 Hz), 1.35 (d, 3H,J=6.8 Hz), 1.20-1.41 (m, 28H), 1.41-1.51 (m, 2H), 3.24-3.37 (m, 1H),3.65-3.73 (m, 1H).

EXAMPLE 41

[0303] (2S,3R)-2-(N,N-Dibenzylamino)-3-eicosanol, 44.

[0304] According to the method of Example 26, from aldehyde 4 (410 mg,1.62 mmol) and 1-bromoheptadecane (2.07 g, 6.47 mmol), alcohol 44 wasobtained as a colorless oil (427 mg, 53% yield).

[0305] R_(f) 0.50 (hexane/EtOAc 5:1);

[0306]¹H NMR (300 MHz, CDCl₃) δ0.93 (t, 3H, J=6.9 Hz), 1.14 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 30H), 1.65-1.80 (m, 2H), 1.94 (br s, 1H), 2.75(quint, 1H, J=6.7 Hz), 3.51 (d, 2H, J=13.8 Hz), 3.56-3.64 (m, 1H), 3.80(d, 2H, J=13.8 Hz), 7.23-7.40 (m, 10H);

[0307]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.6, 29.6,29.7, 31.9, 34.3, 54.8, 57.3, 73.6, 126.8, 128.2, 128.7, 140.2;

[0308] ESMS calcd for C₃₄H₅₆NO (M+H) 494.4, found 494.5.

EXAMPLE 42

[0309] (2S,3R)-2-Amino-3-eicosanol, 3.

[0310] According to the method of Example 27, from N,N-dibenzylamine 44(294 mg, 0.60 mmol), aminoalcohol 3 was obtained as a white solid (140mg, 75% yield).

[0311]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=6.7 Hz), 1.00 (d, 3H,J=6.4 Hz), 1.20-1.40 (m, 30H), 1.45-1.55 (m, 2H), 1.70 (br s, 3H),2.92-3.02 (m, 1H), 3.39-3.49 (m, 1H);

[0312]¹³C NMR (75 MHz, CDCl₃) δ14.1, 16.8, 22.7, 26.2, 29.3, 29.7, 29.8,31.9, 32.5, 50.4, 74.7;

[0313] ESMS calcd for C₂₀H₄₄NO (M+H) 314.3, found 314.3.

EXAMPLE 43

[0314] (2S,3R)-2-Amino-3-eicosanol hydrochloride, 45.

[0315] According to the method of Example 32, from aminoalcohol 3 (12mg, 0.04 mmol), hydrochloride 45 was obtained as a white solid (11 mg,82% yield). ¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.5 Hz), 1.21 (d,3H, J=6.7 Hz), 1.25-1.40 (m, 30H), 1.45-1.60 (m, 2H), 3.26 (qd, 1H,J=6.9, 3.0 Hz), 3.63-3.73 (m, 1H);

[0316]¹³C NMR (75 MHz, CD₃OD) δ12.1, 14.4, 23.7, 27.8, 30.5, 30.6, 30.8,33.1, 34.0, 52.6, 71.7;

[0317] ESMS calcd for C₂₀H₄₄NO (M−Cl) 314.3, found 314.5.

EXAMPLE 44

[0318] (2S,3R)-2-(N,N-Dibenzylamino)-3-heneicosanol, 46.

[0319] According to the method of Example 26, from aldehyde 4 (350 mg,1.38 mmol) and 1-bromooctadecane (1.15 g, 3.45 mmol), alcohol 46 wasobtained as a colorless oil (395 mg, 56% yield).

[0320] R_(f) 0.50 (hexane/EtOAc 5:1);

[0321]¹H NMR (300 MHz, CDCl₃) δ0.91 (t, 3H, J=6.9 Hz), 1.14 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 32H), 1.65-1.75 (m, 2H), 1.80 (br s, 1H), 2.75(quint, 1H, J=6.7 Hz), 3.51 (d, 2H, J=13.9 Hz), 3.56-3.64 (m, 1H), 3.80(d, 2H, J=13.8 Hz), 7.23-7.40 (m, 10H);

[0322]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.7, 31.9,34.3, 54.8, 57.2, 73.6, 126.8, 128.2, 128.7, 140.1;

[0323] ESMS calcd for C₃₅H₅₈NO (M+H) 508.4, found 508.4.

EXAMPLE 45

[0324] (2S,3R)-2-Amino-3-heneicosanol, 47.

[0325] According to the method of Example 27, from N,N-dibenzylamine 46(228 mg, 0.45 mmol), aminoalcohol 47 was obtained as a white solid (125mg, 85% yield).

[0326]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J7 6.9 Hz), 1.00 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 32H), 1.45-1.55 (m, 2H), 1.86 (br s, 3H),2.92-3.02 (m, 1H), 3.39-3.49 (m, 1H);

[0327]¹³C NMR (75 MHz, CDCl₃) δ14.1, 16.8, 22.7, 26.2, 29.3, 29.7, 29.8,31.9, 32.5, 50.4, 74.7;

[0328] ESMS calcd for C₂₁H₄₆NO (M+H) 328.3, found 328.3.

EXAMPLE 46

[0329] (2S,3R)-2-Amino-3-heneicosanol hydrochloride, 48.

[0330] According to the method of Example 32, from aminoalcohol 47 (32.5mg, 0.10 mmol), hydrochloride 48 was obtained as a white solid (32 mg,89% yield).

[0331]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.6 Hz), 1.21 (d, 3H,J=6.9 Hz), 1.25-1.40 (m, 32H), 1.45-1.60 (m, 2H), 3.27 (qd, 1H, J=6.9,3.0 Hz), 3.65-3.73 (m, 1H);

[0332]¹³C NMR (75 MHz, CD₃OD) δ12.1, 14.5, 23.8, 27.0, 30.5, 30.7, 30.7,30.8, 33.1, 34.0, 52.6, 71.6;

[0333] ESMS calcd for C₂₁H₄₆NO (M−Cl) 328.3, found 328.5.

EXAMPLE 47

[0334] (2S,3R)-2-(N,N-Dibenzylamino)-3-docosanol, 49.

[0335] According to the method of Example 26, from aldehyde 4 (380 mg,1.50 mmol) and 1-bromononadecane (1.30 g, 3.75 mmol), alcohol 49 wasobtained as a colorless oil (349 mg, 45% yield).

[0336] R_(f) 0.50 (hexane/EtOAc 5:1);

[0337]¹H NMR (300 MHz, CDCl₃) δ0.91 (t, 3H, J=6.9 Hz), 1.14 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 34H), 1.65-1.75 (m, 2H), 1.81 (br s, 1H), 2.75(quint, 1H, J=6.7 Hz), 3.51 (d, 2H, J=13.9 Hz), 3.56-3.64 (m, 1H), 3.80(d, 2H, J=13.8 Hz), 7.23-7.40 (m, 10H);

[0338]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.7, 31.9,34.3, 54.8, 57.2, 73.6, 126.8, 128.2, 128.7, 140.1;

[0339] ESMS calcd for C₃₆H₆₀NO (M+H) 522.5, found 522.4.

EXAMPLE 48

[0340] (2S,3R)-2-Amino-3-docosanol, 50.

[0341] According to the method of Example 27, from N,N-dibenzylamine 49(206 mg, 0.39 mmol), aminoalcohol 50 was obtained as a white solid (100mg, 74% yield).

[0342]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.9 Hz), 1.00 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 34H), 1.45-1.55 (m, 2H), 1.65 (br s, 3H),2.92-3.02 (m, 1H), 3.39-3.49 (m, 1H);

[0343]¹³C NMR (75 MHz, CDCl₃) δ14.1, 16.8, 22.7, 26.2, 29.3, 29.7, 29.8,31.9, 32.5, 50.4, 74.7;

[0344] ESMS calcd for C₂₂H₄₈NO (M+H) 342.4, found 342.4.

EXAMPLE 49

[0345] (2S,3R)-2-(N,N-Dibenzylamino)-3-tricosanol, 51.

[0346] According to the method of Example 26, from aldehyde 4 (365 mg,1.44 mmol) and 1-bromoeicosadecane (1.30 g, 3.60 mmol), alcohol 51 wasobtained as a colorless oil (317 mg, 41% yield).

[0347] R_(f) 0.50 (hexane/EtOAc 5:1);

[0348]¹H NMR (300 MHz, CDCl₃) δ0.91 (t, 3H, J=6.9 Hz), 1.14 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 36H), 1.65-1.75 (m, 2H), 1.81 (br s, 1H), 2.75(quint, 1H, J=6.7 Hz), 3.51 (d, 2H, J=13.9 Hz), 3.56-3.64 (m, 1H), 3.80(d, 2H, J=13.8 Hz), 7.23-7.40 (m, 10H);

[0349]¹⁴C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.6, 25.8, 9.3, 29.7, 31.9,34.3, 54.7, 57.2, 73.6, 126.8, 128.2, 128.7, 140.1;

[0350] ESMS calcd for C₃₇H₆₂NO (M+H) 536.5, found 536.5.

EXAMPLE 50

[0351] (2S,3R)-2-Amino-3-tricosanol, 52.

[0352] According to the method of Example 27, from N,N-dibenzylamine 51(191 mg, 0.36 mmol), aminoalcohol 52 was obtained as a white solid (103mg, 81% yield).

[0353]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.9 Hz), 1.00 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 36H), 1.45-1.55 (m, 2H), 1.65 (br s, 3H),2.92-3.02 (m, 1H), 3.39-3.49 (m, 1H);

[0354]¹³C NMR (75 MHz, CDCl₁) δ14.1, 16.8, 22.7, 26.2, 29.3, 29.7, 29.8,31.9, 32.5, 50.4, 74.7;

[0355] ESMS calcd for C₂₃H₅₀NO (M+H) 356.4, found 356.4.

EXAMPLE 51

[0356] (3S,4R)-3-(N,N-Dibenzylamino)4octadecanol, 53.

[0357] According to the method of Example 26, from aldehyde 6 (660 mg,2.47 mmol) and 1-bromotetradecane (1.71 g, 6.17 mmol), alcohol 53 wasobtained as a colorless oil (535 mg, 47% yield).

[0358] R_(f) 0.50 (hexane/EtOAc 5:1);

[0359]¹H NMR (300 MHz, CDCl₃) δ0.92 (t, 3H, J=6.6 Hz), 1.02 (t, 3H,J=7.4 Hz), 1.20-1.40 (m, 24H), 1.45-1.60 (m, 3H), 1.70-1.85 (m, 1H),2.27 (br s, 1H), 2.62 (td, 1H, J=7.0, 4.2 Hz), 3.60-3.75 (m, 5H),7.22-7.38 (m, 10H);

[0360]¹³C NMR (75 MHz, CDCl₃) δ12.3, 14.1, 18.1, 22.7, 26.6, 29.4, 29.6,29.7, 31.9, 34.4, 55.2, 62.8, 70.6, 126.9, 128.2, 128.9, 140.1;

[0361] ESMS calcd for C₃₂H₅₂NO (M+H) 466.4, found 466.4.

EXAMPLE 52

[0362] (3S,4R)-3-Amino-4-octadecanol, 54.

[0363] According to the method of Example 27, from N,N-dibenzylamine 53(166 mg, 0.36 mmol), aminoalcohol 54 was obtained as a white solid (100mg, 98% yield).

[0364]¹H NMR (300 MHz, CDCl₃) δ0.89 (t, 3H, J=6.6 Hz), 1.00 (t, 3H,J=7.5 Hz), 1.20-1.40 (m, 26H), 1.45-1.60 (m, 2H), 2.05 (br s, 3H),2.64-2.70 (m, 1H), 3.42-3.50 (m, 1H);

[0365]¹³C NMR (75 MHz, CDCl₃) δ11.0, 14.1, 22.7, 24.8, 26.2, 29.3, 29.6,29.7, 29.8, 31.5, 31.9, 57.1, 74.0;

[0366] ESMS calcd for C₁₈H₄₀NO (M+H) 286.3, found 286.2.

EXAMPLE 53

[0367] (3s,4R)-3-Amino-4-octadecanol hydrocloride, 55.

[0368] According to the method of Example 32, from aminoalcohol 54 (52mg, 0.18 mmol), hydrochloride 55 was obtained as a white solid (38 mg,65% yield).

[0369]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.7 Hz), 1.04 (t, 3H,J=7.4 Hz), 1.25-1.50 (m, 26H), 1.55-1.80 (m, 2H), 3.04-3.12 (m, 1H),3.70-3.80 (m, 1H);

[0370]¹³C NMR (75 MHz, CD₃OD) δ10.6, 14.5, 21.4, 23.8, 27.1, 30.5, 30.6,30.7, 30.8, 33.0, 33.1, 59.0, 71.4;

[0371] ESMS calcd for C₁₈H₄₀NO (M−Cl) 286.3, found 286.2.

EXAMPLE 54

[0372] (3S,4R)-3-(N,N-Dibenzylamino)-4-nonadecanol, 56.

[0373] According to the method of Example 26, from aldehyde 6 (1.0 g,3.7 mmol) and 1-bromopentadecane (6.55 g, 22.5 mmol), alcohol 56 wasobtained as a colorless oil (800 mg, 45% yield).

[0374]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=6.8 Hz), 0.99 (t, 3H,J=7.4 Hz), 1.20-1.35 (m, 26H), 1.40-1.55 (m, 3H), 1.70-1.80 (m, 1H),2.56-2.62 (m, 1H), 3.60-3.75 (m, 5H), 7.26-7.46 (m, 10H).

EXAMPLE 55

[0375] (3S,4R)-3-Amino-4-nonadecanol, 57.

[0376] According to the method of Example 27, from N,N-dibenzylamine 56(400 mg, 0.83 mmol), aminoalcohol 57 was obtained as a white solid (220mg, 88% yield).

[0377]¹H NMR (500, MHz, CD₃OD) δ0.80 (t, 3H, J=7.1 Hz), 0.91 (t, 3H,J=7.5 Hz), 1.15-1.25 (m, 26H), 1.30-1.40 (m, 2H), 1.40-1.50 (m, 1H),1.55-1.65 (m, 1H), 2.70-2.75 (m, 1H), 3.45-3.50 (m, 1H);

[0378]¹³C NMR (125 MHz, CD₃OD) δ11.8, 15.4, 24.5, 24.7, 28.1, 31.4,31.7, 33.9, 34.0, 59.8, 74.3;

[0379] ESMS calcd for C₁₉H₄₂NO (M+H) 300.3, found 300.4.

EXAMPLE 56

[0380] (3S,4R)-3-Amino-4-nonadecanol hydrochloride, 58.

[0381] According to the method of Example 32, from aminoalcohol 57 (20mg, 0.07 mmol), hydrochloride 58 was obtained as a white solid (6 mg,27% yield).

[0382]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.6 Hz), 1.04 (t, 3H,J=7.6 Hz), 1.25-1.50 (m, 28H), 1.55-1.80 (m, 2H), 3.04-3.12 (m, 1H),3.70-3.80 (m, 1H);

[0383]¹³C NMR (75 MHz, CD₃OD) δ10.6, 14.4, 21.4, 23.8, 27.1, 30.5, 30.6,30.8, 33.0, 33.1, 59.0, 71.4;

[0384] ESMS calcd for C₁₉H₄₂NO (M−Cl) 300.3, found 300.5.

EXAMPLE 57

[0385] (3S,4R)-3-(N,N-Dibenzylamino)-4-eicosanol, 59.

[0386] According to the method of Example 26, from aldehyde 6 (600 mg,2.24 mmol) and 1-bromohexadecane (1.37 mL, 4.49 mmol), alcohol 59. wasobtained as a colorless oil (775 mg, 70% yield).

[0387] R_(f) 0.50 (hexane/EtOAc 9:1);

[0388]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=7.1 Hz), 0.95 (t, 3H,J=7.1 Hz), 1.20-1.40 (m, 28H), 1.45-1.60 (m, 3H), 1.70-1.85 (m, 1H),2.22 (br s, 1H), 2.62-2.68 (m, 1H), 3.62-3.73 (m, 5H), 7.24-7.34 (m,10H);

[0389]¹³C NMR (75 MHz, CDCl3) δ12.3, 14.1, 18.1, 22.6, 26.6, 29.3, 29.6,29.7, 31.9, 34.4, 55.1, 62.7, 70.5, 126.9, 128.2, 128.9, 140.1;

[0390] ESMS calcd for C₃₄H₅₆NO (M+H) 494.4, found 494.5.

EXAMPLE 58

[0391] (3S,4R)-3-Amino-4-eicosanol, 60.

[0392] According to the method of Example 27, from N,N-dibenzylamine 59(200 mg, 0.40 mmol), aminoalcohol 60 was obtained as a white solid (104mg, 83% yield).

[0393]¹H NMR (300 MHz, CD₃OD) δ0.87 (t, 3H, J=6.9 Hz), 0.89 (t, 3H,J=6.9 Hz), 1.20-1.40 (m, 30H), 1.45-1.53 (m, 2H), 2.55-3.20 (m, 4H),3.50-3.61 (m, 1H);

[0394] ESMS calcd for C₂₀H₄₄NO (M+H) 314.3, found 314.4.

EXAMPLE 59

[0395] (3S,4R)-3-Amino-4-eicosanol hydrochloride, 61.

[0396] According to the method of Example 32, from aminoalcohol 60 (30.0mg, 0.17 mmol), hydrochloride 61 was obtained as a white solid (20.4 mg,61% yield).

[0397]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=7.4 Hz), 1.04 (t, 3H,J=7.4Hz), 1.25-1.50 (m, 30H), 1.55-1.80 (m, 2H), 3.04-3.12 (m, 1H), 3.70-3.80(m, 1H);

[0398]¹³C NMR (75 MHz, CDCl₃) δ10.5, 14.4, 21.3, 23.7, 27.1, 30.4, 30.6,30.7, 30.8, 32.9, 33.0, 59.0, 71.4;

[0399] ESMS calcd for C₂₀H₄₄NO (M−Cl) 314.3, found 314.5.

EXAMPLE 60

[0400] (3S,4R)-3-(N,N-Dibenzylamino)-4-heneicosanol, 62.

[0401] According to the method of Example 26, from aldehyde 6 (610 mg,2.28 mmol) and 1-bromoheptadecane (1.82 g, 5.70 mmol), alcohol 62 wasobtained as a colorless oil (620 mg, 54% yield).

[0402] R_(f) 0.50 hexane/EtOAc 5:1);

[0403]¹H NMR (300 MHz, CDCl₃) δ0.86 (t, 3H, J=6.9 Hz), 0.94 (t, 3H,J=7.3 Hz), 1.20-1.40 (m, 30H), 1.45-1.55 (m, 3H), 1.70-1.85 (m, 1H),2.24 (br s, 1H), 2.73 (td, 1H, J=7.0, 4.2 Hz), 3.60-3.75 (m, 5H),7.22-7.36 (m, 10H);

[0404]¹³C NMR (75 MHz, CDCl₃) δ12.3, 14.1, 18.1, 22.7, 26.7, 29.4, 29.6,29.7, 31.9, 34.4, 55.2, 62.8, 70.6, 126.9, 128.3, 128.9, 140.1;

[0405] ESMS calcd for C₃₅H₅₈NO (M+H) 508.4, found 508.5.

EXAMPLE 61

[0406] (3S,4R)-3-Amino-4-heneicosanol, 63.

[0407] According to the method of Example 27, from N,N-dibenzylamine 62(295 mg, 0.58 mmol), aminoalcohol 63 was obtained as a white solid (184mg, 97% yield).

[0408]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=7.0 Hz), 0.94 (t, 3H,J=7.4 Hz), 1.20-1.40 (m, 32H), 1.45-1.60 (m, 2H), 1.79 (br s, 3H),2.62-2.70 (m, 1H), 3.42-3.50 (m, 1H);

[0409]¹³C NMR (75 MHz, CDCl₃) δ11.0, 14.1, 22.7, 25.0, 26.2, 29.3, 29.7,29.8, 31.4, 31.9, 57.1, 74.1;

[0410] ESMS calcd for C₂₁H₄₆NO (M+H) 328.3, found 328.4.

EXAMPLE 62

[0411] (3S,4R)-3-Amino-4-heneicosanol hydrochloride, 64.

[0412] According to the method of Example 32, from aminoalcohol 63 (74mg, 0.23 mmol), hydrochloride 64 was obtained as a white solid (51 mg,62% yield).

[0413]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, * 6.9 Hz), 1.04 (t, 3H,J=7.4 Hz), 1.25-1.50 (m, 32H), 1.55-1.80 (m, 2H), 3.04-3.12 (m, 1H),3.70-3.80 (m, 1H);

[0414]¹³C NMR (75 MHz, CD₃OD) δ10.6, 14.5, 21.4, 23.7, 27.1, 30.5, 30.6,30.7, 30.8, 33.0, 33.1, 59.0, 71.4;

[0415] ESMS calcd for C₂₁H₄₆NO (M−Cl) 328.3, found 328.4.

EXAMPLE 63

[0416] (4S,5R)4-(N,N-Dibenzylamino)-5-eicosanol, 65.

[0417] According to the method of Example 26, from aldehyde 11 (123 mg,0.44 mmol) and 1-bromopentadecane (318 mg, 1.09 mmol), alcohol 65 wasobtained as a colorless oil (161 mg, 75% yield).

[0418] R_(f) 0.53 (hexane/EtOAc 5:1);

[0419]¹H NMR (300 MHz, CDCl₃) δ0.89 (t, 3H, J=6.9 Hz), 0.91 (t, 3H,J=7.0 Hz), 1.20-1.40 (m, 28H), 1.40-1.55 (m, 3H), 1.70-1.80 (m, 1H),2.22 (br S, 1H), 2.65-2.72 (m, 1H), 3.60-3.75 (m, 5H), 7.21-7.35 (m,10H);

[0420]¹³C NMR (75 MHz, CDCl₃) δ14.1, 14.4, 20.6, 22.7, 26.7, 27.5, 29.4,29.6, 29.6, 29.7, 31.9, 34.4, 55.2, 60.7, 70.7, 127.0, 128.3, 128.9,140.1;

[0421] ESMS calcd for C₃₄H₅₆NO (M+H) 494.4, found 494.4.

EXAMPLE 64

[0422] (4S,5R)-4-Amino-5-eicosanol, 66.

[0423] According to the method of Example 27, from N,N-dibenzylamine 65(37 mg, 0.075 mmol), aminoalcohol 66 was obtained as a white solid (17mg, 72% yield).

[0424]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.7 Hz), 0.93 (t, 3H,J=6.7 Hz), 1.20-1.40 (m, 30H), 1.45-1.55 (m, 2H), 2.75-2.80 (m. 1H),3.40-3.45 (m, 1H);

[0425]¹³C NMR (75 MHz, CDCl₃) δ14.1, 19.7, 22.7, 26.2, 29.4, 29.7, 31.4,31.9, 34.4, 55.0, 74.4;

[0426] ESMS calcd for C₂₀H₄₄NO (M+H) 314.3, found 314.3.

EXAMPLE 65

[0427] (4S,5R)-4-Amino-5-eicosanol hydrochloride, 67.

[0428] According to the method of Example 32, from aminoalcohol 66 (9mg, 0.03 mmol), hydrochloride 67 was obtained as a white solid (3 mg,30% yield).

[0429]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.9 Hz), 0.99 (t, 3H,J=7.0 Hz), 1.20-1.40 (m, 28H), 1.40-1.65 (m, 4H), 3.08-3.18 (m, 1H),3.65-3.75 (m, 1H);

[0430] ESMS calcd for C₂₀H₄₄NO (M−Cl) 314.3, found 314.5.

EXAMPLE 66

[0431] (3S,4R)-3-(N,N-Dibenzylamino)-2-methyl-4-nonadecanol, 68.

[0432] According to the method of Example 26, from aldehyde 14 (447 mg,1.59 mmol) and 1-bromopentadecane (1.16 g, 4.0 mmol), alcohol 68 wasobtained as a colorless oil (340 mg, 43% yield).

[0433] R_(f) 0.50 (hexane/EtOAc 5:1);

[0434]¹H NMR (300 MHz, CDCl₃) δ0.93 (t, 3H, J=7.0 Hz), 0.96 (d, 3H,J=6.5 Hz), 1.25-1.40 (m, 29H), 1.55-1.70 (m, 2H), 2.19-2.27 (m, 1H),2.56 (dd, 1H, J=9.7, 4.7 Hz), 2.84 (br d, 1H,. J=7.9 Hz), 3.55-3.65 (m,1H), 3.79 (d, 2H, J=13.4 Hz), 3.9.0 (d, 2H, J=13.4 Hz), 7.25-7.38 (m,10H);

[0435]¹³C NMR (75 MHz, CDCl₃) δ14.1, 20.8, 22.7, 23.2, 27.1, 28.2, 29.3,29.6, 29.6, 31.9, 33.2, 56.3, 67.2, 70.3, 127.2, 128.4, 129.1, 139.9;

[0436] ESMS calcd for C₃₄H₅₆NO (M+H) 494.4, found 494.4.

EXAMPLE 67

[0437] (3S,4R)-3-Amino-2-methyl-4-nonadecanol, 69.

[0438] According to the method of Example 27, from N,N-dibenzylamine 68(171 mg, 0.35 mmol), aminoalcohol 69 was obtained as a white solid (90mg, 83% yield).

[0439]¹H NMR (300 MHz, CDCl₃) δ0.85 (t, 3H, J=7.0 Hz), 0.88 (d, 3H,J=6.7 Hz), 0.95 (d, 3H, J=6.7 Hz), 1.20-1.40 (m, 26H), 1.50-1.65 (m,3H), 2.02 (br s, 3H), 2.41 (dd, 1H, J=7.9, 4.7 Hz), 3.54-3.62 (m, 1H);

[0440]¹³C NMR-(75 MHz, CDCl₃) δ14.1, 19.2, 19.8, 22.6, 26.1, 29.3, 29.6,29.7, 29.7, 30.4, 30.8, 31.9, 61.7, 71.5;

[0441] ESMS calcd for C₂₀H₄₄NO (M+H) 314.3, found 314.3.

EXAMPLE 68

[0442] (3S,4R)-3-Amino-2-methyl-4-nonadecanol hydroclorid, 70.

[0443] According to the method of Example 32, from aminoalcohol 69 (68.5mg, 0.22 mmol), hydrochloride 70 was obtained as a white solid (55.5 mg,73% yield).

[0444]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.7 Hz), 1.01 (d, 3H,J=6.7 Hz), 1.05 (d, 3H, J=6.7 Hz), 1.25-1.40 (m, 26H), 1.55-1.70 (m,2H), 1.88-1.96 (m, 1H), 2.84 (dd, 1H, J=8.6, 4.1 Hz), 3.80-3.85 (m, 1H);

[0445]¹³C NMR (75 MHz, CDOD₃) δ14.5, 19.5, 19.9, 23.7, 27.0, 28.7, 30.5,30.6, 30.7, 30.8, 31.1, 33.1, 63.8, 69.5;

[0446] ESMS calcd for C₂₀H₄₄NO (M−Cl) 314.3, found 314.4.

EXAMPLE 69

[0447] (3S,4S,5R)-4-(N,N-Dibenzylamino)-3-methyl-5-eicosanol, 71.

[0448] According to the method of Example 26, from aldehyde 17 (470 mg,1.59 mmol) and 1-bromopentadecane (0.63 mL, 3.18 mmol), alcohol 71 wasobtained as a colorless oil (499 mg, 60% yield).

[0449] R_(f) 0.60 (hexane/EtOAc 9:1);

[0450]¹H NMR (300 MHz, CDCl₃) δ0.85-0.90 (m, 6H), 0.98 (d, 3H, J=7.4Hz), 1.25-1.40 (m, 27H), 1.55-1.60 (m, 2H), 1.86-1.97 (mi, 2H),2.54-2.60 (m,2H), 3.58-3.68 (m, 1H), 3.70 (d, 2H, J=13.7 Hz), 3.85 (d,2H, J=13.7 Hz), 7.25-7.38 (m, 10H);

[0451]¹³C NMR (75 MHz, CDCl₃) δ11.3, 14.1, 16.1, 22.6, 26.8, 28.1, 29.3,29.5, 29.6, 31.8, 33.4, 34.2, 56.1, 65.5, 70.3, 127.1, 128.3, 129.1,138.9;

[0452] ESMS calcd for C₃₅H₅₈NO (M+H) 508.4, found 508.8.

EXAMPLE 70

[0453] (3S,4S,5R)-4-Amino-3-methyl-5-eicosanol, 72.

[0454] According to the method of Example 27, from N,N-dibenzylamine 71(70 mg, 0.13 mmol), aminoalcohol 72 was obtained as a white solid (40mg, 89% yield).

[0455]¹H NMR (300 MHz, CDCl₃) δ0.91-1.10 (m, 6H), 1.15-1.46 (m, 31H),2.45-2.51 (m, 2H), 1.65-1.69 (m, 1H), 2.68-2.72 (m, 1H), 3.62-3.69 (m,1H), 4.25-4.60 (m, 2H);

[0456] ESMS calcd for C₂₁H₄₆NO (M+H) 328.3, found 328.4.

EXAMPLE 71

[0457] (3S,4S,5R)-4-Amino-3-methyl-5-eicosanol hydrochloride, 73.

[0458] According to the method of Example 32, from aminoalcohol 72 (40mg, 0.11 mmol), hydrochloride 73 was obtained as a white solid (32 mg,78% yield).

[0459]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.9 Hz), 0.95 (t, 3H,J=6.9 Hz), 1.20-1.40 (m, 31H), 1.45-1.60 (m, 2H), 1.75-1.85 (m, 1H),3.18-3.23 (m, 1H), 3.90-3.95 (m, 1H), 7.90-8.05 (br s, 3H);

[0460]¹³C NMR (75 MHz, CDCl₃) δ10.5, 14.1, 15.6, 22.6, 25.3, 26.1, 29.3,29.6, 29.7, 31.9, 33.7, 61.6, 70.1;

[0461] ESMS calcd for C₂₁H₄₆NO (M−Cl) 328.3, found 328.4.

EXAMPLE 72

[0462](2S,3R)-1-(4′-Benzyloxyphenyl)-2-(N,N-dibenzylamino)-3-octadecanol, 74.

[0463] According to the method of Example 26, from aldehyde 20 (597 mg,1.37 mmol) and 1-bromopentadecane (999 mg, 3.43 mmol), alcohol 74 wasobtained as a colorless oil (496 mg, 56% yield).

[0464] R_(f) 0.50 (hexane/EtOAc 10:1);

[0465]¹H NMR (300 MHz, CDCl₃) δ0.90 (t, 3H, J=6.7 Hz), 1.25-1.40 (m,26H), 1.55-1.70 (m, 2H), 1.96 (br s, 1H), 2.43 (dd, 1H, J=12.4, 5.2 Hz),2.95-3.07 (m, 2H), 3.65 (d, 2H, J=13.8 Hz), 3.65-3.75 (m, 1H), 3.78 (d,2H, J=13.8 Hz), 5.09 (s, 2H), 6.92 (d, 2H, J=8.6 Hz), 7.07 (d, 2H, J=8.6Hz), 7.20-7.49 (m, 15H);

[0466]¹³C NMR (75 MHz, CDCl₃) δ14.1, 22.7, 26.4, 29.4, 29.5, 29.6, 29.7,31.0, 31.9, 34.6, 55.1, 63.2, 70.1, 71.6, 114.8, 126.9, 127.4, 127.9,128.2, 128.6, 128.8, 130.2,132.8, 137.2, 139.8, 157.1;

[0467] ESMS calcd for C₄₅H₆₂NO₂ (M+H) 648.5, found 648.5.

EXAMPLE 73

[0468] (2S,3R)-2-Amino-1-(4′-hydroxyphenyl)-3-octadecanol, 75.

[0469] According to the method of Example 27, from N,N-dibenzylamine 74(140 mg, 0.22 mmol), aminoalcohol 75 was obtained as a white solid (80mg, 98% yield).

[0470]¹H NMR (300 MHz, CD₃OD) δ0.89 (d, 3H, J=6.6 Hz), 1.25-1.40 (m,26H), 1.50-1.65 (m, 21), 2.35-2.44 (m, 1H), 2.81-2.92 (m, 2H), 3.45-3.50(m, 1H), 6.73 (d, 2H, J=8.2 Hz), 7.03 (d, 2H, J=8.2 Hz);

[0471]¹³C NMR (75 MHz, CD₃OD) δ14.5, 23.7, 27.2, 30.5, 30.8, 30.8, 33.1,33.4, 38.3, 58.7, 74.8, 116.4, 130.9, 131.2, 157.1;

[0472] ESMS calcd for C₂₄H₄₄NO₂ (M+H) 378.3, found 378.3.

EXAMPLE 74

[0473] (2S,3R)-2-Amino-1-(4′-hydroxyphenyl)-3-octadecanol hydrochloride,76.

[0474] According to the method of Example 32, from aminoalcohol 75 (43mg, 0.11 mmol), hydrochloride 76 was obtained as a white solid (10 mg,21% yield).

[0475]¹H NMR (300 MHz, CD₃OD) δ0.90 (d, 3H, J=6.7 Hz), 1.20-1.40 (m,26H), 1.45-1.60 (m, 2H), 2.72 (dd, 1H, J=14.3, 9.3 Hz), 2.92 (dd, 1H,J=14.3, 5.4 Hz),:3.39 (ddd, 1H, J=9.1, 5.5, 3.2 Hz), 3.66-3.75 (m, 1H),6.78 (d, 2H, J=8.6 Hz), 7.10 (d, 2H, J=8.6 Hz);

[0476]¹³C NMR (75 MHz, CD₃OD) δ14.5, 23.8, 27.1, 30.5, 30.6, 30.7, 30.7,30.8, 33.1, 33.6, 59.0, 71.3, 116.8, 127.9, 131.3, 157.9;

[0477] ESMS calcd for C₂₄H₄₄NO₂ (M−Cl) 378.3, found 378.3.

EXAMPLE 75

[0478] (4S,5R)-1,4-Bis-(N,N-dibenzylamino)-5-eicosanol, 77.

[0479] According to the method of Example 26, from aldehyde 23 (503 mg,1.05 mmol) and 1-bromopentadecane (768; mg, 2.64 mmol), alcohol 77 wasobtained as a colorless oil (350 mg, 48% yield).

[0480] R_(f) 0.50 (hexane/EtOAc 5:1);

[0481]¹H NMR (300 MHz, CDCl₃) δ0.90 (t, 3H, J=6.7 Hz), 1.25-1.40 (m,28H), 1.40-1.60 (m, 2H), 1.60-1.75 (m, 2H), 1.97 (br s, 1H), 2.43 (t,2H, J=6.7 Hz), 2.56-2.62 (m, 1H), 3.57 (s, 4H), 3.61 (d, 2H, J=13.8 Hz),3.65-3.75 (m, 1H), 3.67 (d, 2H, J=13.8 Hz), 7.20-7.40 (m, 20H);

[0482]¹³C NMR (75 MHz, CDCl₃) δ14.1, 22.7, 23.1, 25.1, 26.6, 29.4, 29.6,29.7, 31.9, 34.6, 53.9, 55.1, 58.4, 61.2, 70.9, 126.8, 127.0, 128.1,128.3, 128.8, 128.9, 139.8, 140.1;

[0483] ESMS calcd for C₄₈H₆₉N₂O (M+H) 689.5, found 689.5.

EXAMPLE 76

[0484] (4S,5R)-1,4-Diamino-5-eicosanol, 78.

[0485] According to the method of Example 27, frombis-(N,N-dibenzylamine) 77 (105 mg, 0.15 mmol), diaminoalcohol 78 wasobtained as a white solid (45 mg, 91% yield).

[0486]¹H NMR (300 MHz, CD₃OD) δ0.88 (d, 3H, J=6.7 Hz), 1.25-1.45 (m,28H), 1.60-1.75 (m, 4H), 2.65-2.85 (m, 3H), 3.42-3.52 (m, 1H);

[0487]¹³C NMR (75 MHz, CD₃OD) δ14.4, 23.7, 26.9, 27.2, 28.8, 30.5, 30.8,33.1, 33.4, 41.1, 56.9, 74.6;

[0488] ESMS calcd for C₂₀H₄₅N₂O (M+H) 329.3, found 329.3.

EXAMPLE 77

[0489] (4S,5R)-1,4-Diamino-5-eicosanol dihydrochloride, 79.

[0490] According to the method of Example 32, from diaminoalcohol 78 (40mg, 0.12 mmol) dihydrochloride 79 was obtained as a white solid (30 mg,61% yield).

[0491]¹H NMR (300 MHz, CD₃OD) δ0.89 (d, 3H, J=6.5 Hz), 1.25-1.40 (m,26H), 1.45-1.60 (m, 3H), 1.70-1.95 (m, 3H), 2.98 (t, 2H, J=7.0 Hz),3.20-3.25 (m, 1H), 3.72-3.80 (m, 1H);

[0492]¹³C NMR (75 MHz, CD₃OD) δ14.5, 23.7, 25.1, 25.5, 27.1, 30.5, 30.7,30.8, 30.8, 33.1, 33.3, 40.4, 56.9, 71.5;

[0493] ESMS calcd for C₂₀H₄₅N₂O (M−HCl₂) 329.3, found 329.4.

EXAMPLE 78

[0494] (2R,3S)-2-(N,N-Dibenzylamino)-3-octadecanol, 80.

[0495] According to the method of Example 26, from aldehyde 26 (445 mg,1.76 mmol) and 1-bromopentadecane (1.28 g, 4.39 mmol), alcohol 80 wasobtained as a colorless oil (422 mg, 52% yield).

[0496] R_(f) 0.50 (hexane/EtOAc 5:1);

[0497]¹H NMR (300 MHz, CDCl₃) δ0.91 (t, 3H, J=6.9 Hz), 1.12 (d, 3H,J=6.7 Hz), 1.20-1.40 (m, 26H), 1.65-1.75 (m, 2H), 1.85 (br s, 1H), 2.73(quint, 1H, J=6.4 Hz), 3.49 (d, 2H, J=13.9 Hz), 3.57-3.65 (m, 1H), 3.78(d, 2H, J=13.8 Hz), 7.21-7.38 (m, 10H);

[0498]¹³C NMR (75 MHz, CDCl₃) δ8.6, 14.1, 22.7, 25.9, 29.3, 29.6, 29.7,31.9, 34.4, 54.8, 57.3, 73.6, 126.9, 128.2, 128.8, 140.2;

[0499] ESMS calcd for C₃₂H₅₂NO (M+H) 466.4, found 466.4.

EXAMPLE 79

[0500] (2R,3S)-2-Amino-3-octadecanol, 81.

[0501] According to the method of Example 27, from N,N-dibenzylamine 80(256 mg, 0.55 mmol), aminoalcohol 81was obtained as a white solid (175mg, 92% yield).

[0502]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=7.0 Hz), 1.02 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 26H), 1.45-1.55 (m, 2H), 1.85 (br s, 3H),2.94-3.04 (m, 1H), 3.42-3.52 (m, 1H);

[0503]¹³C NMR (75 MHz, CDCl₃) δ14.1, 16.3, 22.7, 26.2, 29.3, 29.7, 31.9,32.5, 50.4, 74.2;

[0504] ESMS calcd for C18H₄₀NO (M+H) 286.3, found 286.2.

EXAMPLE 80

[0505] (2S,3R)-O-Acetyl-2-(N,N-dibenzylamino)-3-octadecanol, 82.

[0506] To a solution of alcohol 39 (48.5 mg. 0.104 mmol) in CH₂Cl₂ (1.0mL) at room temperature, pyridine (25 μL, 0.313 mmol), Ac₂O (29 μL,0.313 mmol) and DMAP (ca. 5 mg, cat.) were added. The reaction wasstirred for 4 h, and then the solvents were evaporated in vacuo. Thecrude was purified by column chromatography on silica (hexane/EtOAc10: 1) to obtain acetate 82 as a colorless oil (46 mg, 87% yield).

[0507] R_(f) 0.62 (hexane/EtOAc 5:1);

[0508]¹H NMR (300 MHz, CDCl₃) δ0.91 (t, 3H, J=6.8 Hz), 1.07 (d, 3H,J=6.6 Hz), 1.20-1.35 (m, 26H), 1.40-1.50 (m, 1H), 1.75-1.85 (m, 1H),2.02 (s, 3H), 2.81 (quint, 1H, J=7.1 Hz), 3.46 (d, 2H, J=13.9 Hz), 3.76(d, 2H, J=13.9 Hz), 5.11 (dt, 1H, J=7.5, 4.2 Hz), 7.22-7.39 (m, 10H);

[0509]¹³C NMR (75 MHz, CDCl₃) δ8.7, 14.1, 21.2, 22.7, 24.8, 29.3, 29.5,29.6, 29.7, 31.9, 32.0, 54.2, 54.7, 75.2, 126.8, 128.1, 12.8, 140.0,170.8;

[0510] ESMS calcd for C₃₄H₅₄NO₂ (M+H) 508.4, found 508.5.

EXAMPLE 81

[0511] (2S,3R)-2-(N-Acetylamino)-3-octadecanol, 83.

[0512] According to the method of Example 27, from N,N-dibenzylamine 82(41 mg, 0.081 mmol), acetamide 83 was obtained as a white solid (13 mg,49% yield).

[0513]¹H NMR (300 MHz, CDCl₃) δ0.89 (t, 3H, J=7.1 Hz), 1.09 (d, 3H,J=6.8 Hz), 1.20-1.35 (m, 26H), 1.45-1.55 (m, 2H), 1.99 (s, 3H), 2.15 (brs, 1H), 3.60-3.65 (m, 1H), 4.00 (dquint, 1H, J=7.4, 2.4 Hz), 5.84 (br d,1H, J=7.1 Hz);

[0514]¹³C NMR (75 MHz, CDCl₃) δ13.9, 14.1, 22.7, 23.5, 26.0, 29.4, 29.6,29.7, 31.9, 33.6, 49.5, 74.2, 82.4, 170.0;

[0515] ESMS calcd for C₂₀H₄₁NO₂Na (M+Na) 350.3, found 350.3.

EXAMPLE 82

[0516] (2S,3R)-2-(N,N-Dibenzylamino)-3-(methoxy)-octadecane, 84.

[0517] To a solution of alcohol 39 (322 mg, 0.69 mmol) in DMF (3.5 mL)at room temperature, NaH (60% mineral dispersion, 69 mg, 1.73 mmol) andMeI (0.22 mL, 3.46 mmol) were added. After stirring for 16 h, themixture was quenched with H₂O (15 mL), extracted with Et₂O (3×15 mL),dried over Na₂SO₄ and concentrated in vacuo. The crude was purified bycolumn chromatography on silica (hexane/EtOAc 15:1) to obtain 84 as acolorless oil (110 mg, 33% yield).

[0518] R_(f) 0.56 (hexane/EtOAc 10:1);

[0519]¹H NMR (300 MHz, CDCl₃) δ0.94 (t, 3H, J=6.7 Hz), 1.08 (d, 3H,J=6.7 Hz), 1.20-1.40 (m, 26H), 1.55-1.70 (m, 2H), 2.74 (quint, 1H, J=6.7Hz), 3.27 (q, 1H, J=6.4 Hz), 3.36 (s, 3H), 3.50 (d, 2H, J=13.8 Hz), 3.77(d, 2H, J=13.8 Hz), 7.23-7.42 (m, 10H);

[0520]¹³C NMR (75 MHz, CDCl₃) δ8.2, 14.1, 22.7, 24.4, 29.4, 29.7, 29.7,29.7, 30.0, 30.6, 31.9, 54.3, 54.7, 57.4, 83.7, 126.7, 128.1, 128.8,140.4;

[0521] ESMS calcd for C₃₃H₅₄NO (M+H) 480.4, found 480.7.

EXAMPLE 83

[0522] (2S,3R)-2-Amino-3-(methoxy)-octadecane, 85.

[0523] According to the method of Example 27, from N,N-dibenzylamine 84(54 mg, 0.11 mmol), amine 85 was obtained as a white solid (14 mg, 42%yield).

[0524] R_(f) 0.10 (hexane/EtOAc 1:1);

[0525]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.6 Hz), 1.03 (d, 3H,J=6.7 Hz), 1.20-1.35 (m, 26H), 1.40-1.55 (m, 2H); 1.96 (br s, 2H),2.94-3.00 (m, 1H), 3.03-3.10 (m, 1H), 3.38 (s, 3H);

[0526]¹³C NMR (75 MHz, CDCl₃) δ14.1, 18.3, 22.7, 26.0, 29.1, 29.3, 29.6,29.6, 29.7, 29.9, 31.9, 47.9, 57.9, 75.0, 85.7;

[0527] ESMS calcd for C₁₉H₄₂NO (M+H) 300.3, found 300.5.

EXAMPLE 84

[0528] (2S,3S)-2-(N,N-Dibenzylamino)-3-chloro-octadecane, 86.

[0529] To a cold (0° C.) solution of alcohol 39 (24 mg, 0.051 mmol) in 1mL of pyridine, POCl₃ (0.019 mL, 0.206 mmol) was added dropwise. Afterstirring at room temperature for 3 h, 0.2 mL of H₂O were added and thesolvent was evaporated in vacuo. The crude was purified by columnchromatography on silica (hexane/EtOAc 10:1) to give chloride 86 as acolorless oil (14 mg, 56% yield).

[0530] R_(f) 0.56 (hexane/EtOAc 10:1);

[0531]¹H NMR (300 MHz, CDCl₃) δ0.89 (t, 3H, J=6.6 Hz), 1.20-1.55 (m,30H), 2.00-2.10 (m, 1H), 2.87 (quint, 1H, J=7.0 Hz), 3.47 (d, 2H, J=13.8Hz), 3.75 (d, 2H, J=13.6 Hz), 3.98 (td, 1H, J=8.1, 3.5 Hz), 7.21-7.36(m, 10H);

[0532]¹³C NMR (75 MHz, CDCl₃) δ10.2, 14.1, 22.7, 26.0, 29.2, 29.4, 29.5,29.6, 29.7, 31.9, 35.6, 54.3, 57.3, 66.9, 126.9, 128.2, 128.8, 139.8;

[0533] ESMS calcd for C₃₂H₅₁ClN (M+H) 484.4, found 484.3.

EXAMPLE 85

[0534] (2S,3S)-2-Amino-3-chloro-octadecane, 87.

[0535] According to the method of Example 27, from N,N-dibenzylamine 86(13 mg, 0.027 mmol), amine 87 was obtained as a white sohd (3 mg, 37%yield).

[0536] R_(f) 0.10 (EtOAc); ¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=6.6Hz), 1.12 (d, 3H, J=6.6 Hz), 1.20-1.70 (m, 30H), 3.09 (qd, 1H, J=6.2,3.4 Hz), 3.90 (td, 1H, J=6.5, 3.5 Hz);

[0537] ESMS calcd for C₁₈H₃₈N (M−Cl) 268.3, found 268.2.

EXAMPLE 86

[0538](2S,3R)-2-(N,N-Dibenzylamino)-O-(dimethylphosphate)-3-octadecanol, 88.

[0539] To a solution of alcohol 39 (44 mg, 0.095 mmol) and CBr4 (47 mg,0.142 mmol) in 0.3 mL of pyridine, (MeO)₃P (0.022 mL, 0.189 mmol) wasadded dropwise. After stirring at room temperature for 24 h, the mixturewas diluted with EtOAc (10 mL), washed successively with 5% HCl (10 mL),NaHCO₃ (10 mL, sat. aq.) and brine (10 mL), dried over Na₂SO₄ andconcentrated in vacuo. The crude was purified by column chromatographyon silica (hexane/EtOAc 10:1 to 2:1) to give dimethyl phosphate 88 as acolorless oil (20 mg, 37% yield) together with unreacted alcohol (25 mg,57% yield).

[0540] R_(f) 0.31 (hexane/EtOAc 2:1);

[0541]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=6.5 Hz), 1.16 (d, 3H,J=6.5 Hz), 1.20-1.40 (m, 26H), 1.65-1.80 (m, 2H), 2.84 (quint, 1H, J=6.9Hz), 3.40 (d, 2H, J=13.8 Hz), 3.69 (dd, 3H, J=2.3, 0.5 Hz), 3.73 (dd,3H, J=2.3, 0.5 Hz), 3.73 (d, 2H, J=13.6 Hz), 4.47 (ddd, 1H, J=12.8, 7.4,4.9 Hz), 7.20-7.34 (m, 10H);

[0542]¹³C NMR (75 MHz, CDCl₃) δ8.5, 14.1, 22.7, 23.4, 29.3, 29.5, 29.6,29.6, 29.7, 31.9, 32.6, 54.0 (d), 54.1 (d), 54.2, 81.7 (d), 126.9,128.2, 128.9, 139.8;

[0543] ESMS calcd for C₃₄H₅₇NO₄P (M+H) 574.4, found 574.4.

EXAMPLE 87

[0544] (2S,3R)-2-Amino-O-(dimethylphosphate)-3-octadecanol, 1, 89.

[0545] According to the method of Example 27, from N,N-dibenzylamine 88(16 mg, 0.028 mmol), amine 89 was obtained as a white solid (6 mg, 55%yield).

[0546] R_(f) 0.32 (EtOAc/MeOH 5:1);

[0547]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=6.6 Hz), 1.08 (d, 3H,J=6.6 Hz), 1.20-1.40 (m, 26H), 1.45-1.55 (m, 1H), 1.60-1.70 (m, 1H),1.97 (br s, 2H), 3.12-3.20 (m, 1H), 3.76 (s, 3H), 3.80 (s, 3H),4.24-4.34 (m, 1H);

[0548] ESMS calcd for C₂₀H₄₅NO₄P (M+H) 394.3, found 394.3.

EXAMPLE 88

[0549] (2S,3S)-2-(N-Benzyloxycarbonylamino)-3-octadecanol, 90.

[0550] According to the method of Example 26, from aldehyde 28 (640 mg,3.1 mmol) and 1-bromopentadecane (5.0 g, 17.2 mmol), alcohol 90 wasobtained as a colorless oil (690 mg, 53% yield).

[0551]¹H NMR (500 MHz, CDCl₃) δ0.88 (t, 3H, J=7.1 Hz), 1.20 (d, 3H,J=6.8 Hz), 1.20-1.35 (m, 26H), 1.40-1.50 (m, 2H), 1.74 (br s, 1H),3.48-3.52 (m, 1H), 3.70-3.75 (m, 1H), 4.90-4.95 (m, 1H), 5.10 (s, 2H),7.30-7.36 (m, 5H).

EXAMPLE 89

[0552] (2S,3S)-2-Amino-3-octadecanol, 91.

[0553] To a solution of N-benzyloxycarbonylamine 90 (330 mg, 0.79 mmol)in MeOH (40 mL) at room temperature, Pd—C (10% wt, 100 mg, 0.09 mmol)was added. The mixture was purged with a stream of dry Ar, and then H₂.The reaction was stirred overnight under a H₂ atmosphere (1 atm). Thecatalyst was filtered off through a 0.45 μm teflon filter inpolypropylene housing, washing the filter with MeOH (50 mL) and thesolvent was evaporated in vacuo. The crude was purified by columnchromatography on silica (90:10 CH₂Cl₂/MeOH to 100% MeOH) to obtainaminoalcohol 91 as a white solid (200 mg, 89% yield).

[0554]¹H NMR (500 MHz, CD₃OD) δ0.80 (t, 3H, J=7.2 Hz), 0.98 (d, 3H,J=6.5 Hz), 1.15-1.30 (m, 26H); 1.40-1.45 (m, 2H), 2.62-2.65 (m, 1H),3.10-3.15 (m, 1H);

[0555]¹³C NMR (125 MHz, CD₃OD) δ14.8, 19.2, 24.1, 27.2, 20.9, 31.1,33.5, 35.0, 53.0, 77.1;

[0556] ESMS calcd for C₁₈H₄₀NO (M+H) 286.3, found 286.4.

EXAMPLE 90

[0557] (3S,4S)-3-(N-Benzyloxycarbonylamino)-4-nonadecanol, 92.

[0558] According to the method of Example 26, from aldehyde 8 (680 mg,3.1 mmol) and 1-bromopentadecane (6.55 g, 22.5 mmol), alcohol 92 wasobtained as a colorless oil (800 mg, 60% yield).

[0559]¹H NMR (500 MHz, CDCl₃) δ0.88 (t, 3H, J=7.1 Hz), 0.96 (t, 3H,J=7.4 Hz), 1.20-1.35 (m, 26H), 1.40-1.45 (m, 2H), 1.55-1.60 (m, 1H),1.65-1.70 (m, 1H), 3.46-3.52 (m, 1H), 3.60-3.65 (m, 1H), 4.91 (d, 1H,J=9.3 Hz), 5.11 (s, 2H), 7.30-7.36 (m, 5H).

EXAMPLE 91

[0560] (3S,4S)-3-Amino-4-nonadecanol, 93.

[0561] According to the method of Example 89, fromN-benzyloxycarbonylamine 92 (230 mg, 0.53 mmol), aminoalcohol 93 wasobtained as a white solid (140 mg, 89% yield).

[0562]¹H NMR (500 MHz, CD₃OD) δ0.80 (t, 3H, J=7.1 Hz), 0.93 (t, 3H,J=7.5 Hz), 1.15-1.25 (m, 26H), 1.30-1.40 (m, 2H), 1.40-1.50 (m, 1H),1.65-1.75 (m, 1H), 2.80-2.85 (m, 1H), 3.45-3.50 (m, 1H);

[0563]¹³C NMR (125 MHz, CD₃OD) δ10.0, 14.4, 23.7, 24.1, 26.6, 30.5,30.6, 30.8, 33.1, 34.9, 58.8, 70.5;

[0564] ESMS calcd for C₁₉H₄₂NO (M+H) 300.3, found 300.4.

EXAMPLE 92

[0565] (2S,3-S)-2-(N-tert-Butoxycarbonylamino)-3-octadecanol, 94.

[0566] To a solution of aminoalcohol 91 (46 mg, 0.. 16 mmol) in CH₂Cl₂(1.6 mL) at room temperature, Boc20 (42 mg, 0.19 mmol) was added. Afterstirring for 3.5 h, the solvent was removed in vacuo to obtain 94 as awhite solid (62 mg, 100% yield).

[0567] R_(f) 0.35 (hexane/EtOAc 5:1);

[0568]¹H NMR (300 MHz, CDCl₃) δ0.86 (t, J=6.5 Hz, 3H), 1.15 (d, J=6.8Hz, 3H), 1.20-1.40 (m, 26H), 1.43 (s, 9H), 1.45-1.60 (m, 2H), 3.40-3.50(m, 1H), 3.55-3.65 (m, 1H), 4.75 (d, 1H, J=8.8 Hz);

[0569]¹³C NMR (75 MHz, CDCl₃) δ14.1, 18.3, 22.7, 25.6, 27.4, 28.4, 29.3,29.6, 29.6, 29.7, 31.9, 34.2, 50.5, 74.9, 156.2.

EXAMPLE 93

[0570] (2S,3R)-3-Azido-2-(N-tert-butoxycarbonylamino)-octadecane, 95.

[0571] To a cold (0° C.) solution of alcohol 94 (48 mg, 0.12 mmol) inCH₂Cl₂ (1.25 mL), Et₃N (52 μL, 0.37 mmol) and MsCl (24 μL, 0.31 mmol)were added. After stirring for 2 h, the mixture was quenched with H₂O(10 mL), extracted with CH₂Cl₂ (3×10 mL), dried over Na₂SO₄ andconcentrated in vacuo. The crude mesylate was dissolved in DMF (0.65 mL)and NaN₃ (40.5 mg, 0.62 mmol) was added. The mixture was stirred at 120C. for 3 h and then quenched with H₂O (10 mL), extracted with Et₂O (3×10mL), dried over Na₂SO₄ and concentrated in vacuo. The crude was purifiedby column chromatography on silica (hexane/EtOAc 10:1 to. 5:1) to obtainazide 95 as a colorless oil (25 mg, 49% yield).

[0572] R_(f) 0.31 (hexane/EtOAc 10:1);

[0573]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.6 Hz), 1.06 (d, 3H,J=6.7 Hz), 1.20-1.40 (m, 26H), 1.44 (s, 9H), 1.45-1.55 (m, 2H),3.50-3.58 (m, 1H), 3.70-3.80 (m, 1H), 4.68 (br d, 1H, J=7.7 Hz);

[0574]¹³C NMR (75 MHz, CDCl₃) δ14.1, 14.4, 22.7, 26.5,.28.2, 28.4, 29.3,29.4, 29.4, 29.5, 29.6, 29.6, 29.7, 31.4, 31.9, 49.3, 66.5, 155.0.

EXAMPLE 94

[0575] (2S,3R)-3-Amino-2-(N-tert-butoxycarbonylamino)-octadecane, 96.

[0576] To a solution of azide 95 (25 mg, 0.06 mmol) in MeOH (1.5 mL) atroom temperature, Pd—C (10% wt, 16 mg, 0.015 mmol) was added. Themixture was purged with a stream of dry Ar, and then H₂. The reactionwas stirred overnight under a H₂ atmosphere (1 atm). The catalyst wasfiltered off through a 0.45 μm teflon filter in polypropylene housing,washing the filter with MeOH (15 mL) and the solvent was evaporated invacuo to obtain amine 96 as a white solid (22 mg, 94% yield).

[0577] R_(f) 0.12 (hexane/EtOac 1.10); ¹H NMR (300 MHz, CDCl₃) δ0.86 (t,3H, J=6.5 Hz), 1.02 (d, 3H, J=6.7 Hz), 1.20-1.40 (m, 26H), 1.43 (s, 9H),1.45-1.55 (m, 2H), 2.0.5 (br s, 2H), 2.72-2.82 (m, 1H), 3.60-3.70 (m,1H), 5.00-5.10 (m, 1H);

[0578]¹³C NMR (75 MHz, CDCl₃) δ14.1, 22.7, 26.5, 28.4, 29.3, 29.7, 31.9,34.8, 49.7, 54.8, 155.4;

[0579] ESMS calcd for C₂₃H₄₉N₂O₂ (M+H) 385.4, found 385.4.

EXAMPLE 95

[0580] (2S,3R)-2,3-Diamino-octadecane dihydrochloride, 97.

[0581] To a solution of N-Boc derivative 96 (22 mg, 0.057 mmol) indioxane (0.4 mL), anhydrous HCl solution in dioxane (5.3M, 0.43 mL, 2.29mmol) was added. After stirring at room temperature for 5 h, the solventwas removed in vacuo. The resulting solid was washed with dioxane toobtain dihydrochloride 97 as a white solid (11.5 mg, 56% yield).

[0582]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.4 Hz), 1.20-1.45 (m,26H), 1.42 (d, 3H, J=7.0 Hz), 1.65-1.80 (m, 2H), 3.42-3.48 (m, 1H),3.58-3.66 (m, 1H);

[0583]¹³C NMR (75 MHz, CD₃OD) δ14.3, 14.4, 23.7, 26.3, 30.4, 30.5, 30.7,30.7, 30.8, 33.1, 55.1;

[0584] ESMS calcd for C₁₈H₄₁N₂ (M−HCl₂) 285.3, found 285.3.

EXAMPLE 96

[0585] (2S,3R)-2-(N-tert-Butoxycarbonylamino)-3-octadecanol, 98.

[0586] According of the method of Example 92, from aminoalcohol 1 (82.5mg, 0.30 mmol) N-Boc derivative 98 was obtained as a white solid (110mg, 95% yield).

[0587] R_(f) 0.35 (hexane/EtOAc 5:1);

[0588]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.9 Hz), 1.09 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 26H), 1.45 (s, 9H), 1.49-1.60 (m, 2H),2.01-2.09 (m, 1H), 3.55-3.69 (m, 3H), 4.61-4.72 (m, 1H);

[0589]¹³C NMR (75 MHz, CDCl₃) δ14.1, 14.2, 22.6, 26.0, .28.3, 29.3,29.6, 31.9, 33.4, 50.5, 74.4, 172.1;

[0590] ESMS calcd for C₂₃H₄₇NO₃Na (M+Na) 408.4, found 408.3.

EXAMPLE 97

[0591](2S,3R)-2-(N-tert-Butoxycarbonylamino)-O(2,2,2-trifluoroacetyl)-3-octadecanol,99.

[0592] To a solution of alcohol 98 (54 mg, 0. 14 mmol) in CH₂Cl₂ (6.0mL) at room temperature, trifluoroacetic anhydride (28 μL, 0.14 mmol),pyridine (22 μL) 0.42 mmol) and DMAP (1.7 mg, 0.01 mmol) were added.After stirring for 1 h, the reaction was quenched with H₂O (10 mL),extracted with CH₂Cl₂ (3×10 mL), dried over Na₂SO₄ and concentrated invacuo. The crude was purified by column chromatography on silica(hexane/AcOEt 9:1) to obtain trifluoroacetate 99 as a white solid (17mg, 25% yield).

[0593] R_(f) 0.24 (hexane/AcOEt 9:1);

[0594]¹H NMR (300 MHz, CD₃OD) δ0.80 (t, 3H, J=6.5 Hz), 1.08 (d, 3H,J=6.5 Hz) 1.18-1.36 (m, 26H), 1.41 (s, 9Hi), 1.52-1.61 (m, 2H),3.87-3.92 (m, 1H), 4.39-4.44 (m, 1H), 4.98-5.21 (m, 1H);

[0595] ESMS calcd for C₂₅H₄₆F₃NO₄Na (M+Na) 504.3, found 504.4.

EXAMPLE 98

[0596] (2S,3R)-2-Ammonium-O-(2,2,2-trifluoroacetyl)-3-octadecanoltrifluoroacetate, 100.

[0597] To a solution of N-Boc derivative 99 (17 mg, 0.03 mmol) in CH₂Cl₂(4 mL) at room temperature, trifluoroacetic acid (1.0 mL) was added.After stirring for 1 h, the solvents were removed in vacuo to obtain 100as a white solid (16 mg, 94% yield).

[0598] R_(f) 0.24 (hexane/AcOEt 9:1);

[0599]¹H NMR (300 MHz, CD₃OD) δ0.80 (t, 3H, J=6.1 Hz), 1.18-1.25 (m,26H), 1.28 (d, 3H, J=6.5Hz), 1.49-1.56 (m, 1H), 1.64-1.69 (m, 1H), 3.51(m, 1H), 5.27 (m, 1H), 7.94 (m, 1H);

[0600]¹³C NMR (75 MHz, CDCl₃) δ12.1, 21.4, 22.7, 25.9, 26.2, 26.3, 26.4,26.6, 27.4,28.9,49.7, 79.0, 101.3, 111.4 161.1;

[0601] ESMS calcd for C₁₈H₃₉NO (M−C₄F₆O₃) 286.5, found 286.2.

EXAMPLE 99

[0602] (2S,3R)-O-Acetyl 2-(N-tert-butoxycarbonylamino)-3-octadecanol,101.

[0603] According of the method of Example 80, from alcohol 98 (20 mg,0.052 mmol), acetate 101 was obtained as a white solid (18.5 mg, 83%yield).

[0604] R_(f) 0.47 (hexane/EtOAc 5:1);

[0605]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.9 Hz), 1.08 (d, 3H,J=6.9 Hz), 1.20-1.35 (m, 26H), 1.43 (s, 9H), 1.45-1.55 (m, 2H), 2.06 (s,3H), 3.79-3.89 (m, 1H), 4.60 (br d, 1H, J=7.7 Hz), 4.85 (dt, 1H, J=7.2,4.9 Hz);

[0606]¹³C NMR (75 MHz, CDCl₃) δ14.1, 15.3, 21.1, 22.7, 25.5, 28.4, 29.3,29.4, 29.5, 29.6, 29.6, 29.7, 30.7, 31.9, 48.3, 79.3, 155.1, 171.0;

[0607] ESMS calcd for C₂₅H₄₉NO₄Na (M+Na) 450.4, found 450.4.

EXAMPLE 100

[0608] (2S,3R)-O-Acetyl-2-amino-3-octadecanol hydrochloride, 102.

[0609] According to the method of Example 95, from N-Boc derivative 101(13.7 mg, 0.032 mmol) hydrochloride 102 was obtained as a white solid (9mg, 77% yield).

[0610]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.6 Hz), 1.20-1.40 (m,29H), 1.55-1.65 (m, 2H), 2.12 (s, 3H), 3.49 (qd, 1H, J=6.7, 2.4 Hz),5.07 (ddd, 1H, J: 8.7,-5.0, 2.6 Hz);

[0611]¹³C NMR (75-MHz, CD₃OD) δ12.9, 14.5, 20.9, 23.8, 26.5, 30.3, 30.5,30.5, 30.7, 30.8, 31.3, 33.1, 51.1, 74.3, 172.5;

[0612] ESMS calcd for C₂₀H₄₂NO₂ (M−Cl) 328.3, found 328.3.

EXAMPLE 101

[0613] (2S,3S)-3-Azido-2-(N-tert-butoxycarbonylamino)-octadecane, 103.

[0614] According to the method of Example 93, from alcohol 98 (50 mg,0.13 mmol), azide 103 was obtained as a colorless oil (39 mg, 73%yield).

[0615] R_(f) 0.64 (hexane/EtOAc 10:1);

[0616]¹H NMR (300 MHz, CD₃OD) δ0.87 (t, 3H, J=6.8 Hz), 1.18 (d, 3H,J=6.8 Hz), 1.20-1.39 (m, 26H), 1.43 (s, 9H), 1.53-1.61 (m, 2H),3.30-3.36 (m, 1H), 3.55-3.97 (m, 1H), 4.50 (d, 1H, J=9.2 Hz);

[0617] ESMS calcd for C₂₃H₄₆N₄O₂Na (M+Na) 433.3, found 433.4.

EXAMPLE 102

[0618] (2S,3S)-3-Amino-2-(N-tert-butoxycarbonylamino)- octadecane, 104.

[0619] According to the method of Example 94, from azide 103 (15 mg,0.03 mmol), amine 104 was obtained as a colorless oil (13 mg, 92%yield).

[0620]¹H NMR (300 MHz, CD₃OD) δ0.87 (t, 3H, J=6.8 Hz), 1.10 (d, 3H,J=6.8 Hz), 1.21-1.40 (m, 26H), 1.43 (s, 9H), 1.45-1.47 (m, 2H),2.70-2.75 (m, 1H), 3.60-3.55 (m, 1H), 4.90 (d, 1H, J=6.8 Hz);

[0621] ESMS calcd for C₂₃H₄₉N₂O₂ (M+H) 385.4, found 385.4.

EXAMPLE 103

[0622] (2S,3 S)-2,3-Diamino-octadecane dihydrochloride, 105.

[0623] According to the method of Example 95, from N-Boc derivative 104(13 mg, 0.03 mmol), dihydrochloride 105 was obtained as a white solid(11 mg, 75% yield).

[0624]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.8 Hz), 1.35 (d, 3H,J=6.8 Hz), 1.25-1.40 (m, 26H), 1.56-1.72 (m, 2H), 3.49-3.56 (m, 1H),3.70-3.74 (m, 1H);

[0625]¹³C NMR (75 MHz, CD₃OD) δ13.1, 14.4, 22.7, 26.5, 27.8, 30.5, 30.8,33.1, 54.1;

[0626] ESMS calcd for C₁₈H₄₁N₂ (M−HCl₂) 285.3, found 285.4.

EXAMPLE 104

[0627] (2S,3R)-2-(N,N-Dimethylamino)-3-octadecanol, 106.

[0628] A mixture of aminoalcohol 1 (100 mg, 0.35 mmol), formaldehyde(37% w/w, aq. 142 mg, 1.75 mmol), NaB(OAc)₃H (370 mg, 1.75 mmol) and(CH₂Cl)₂ (2 mL) was stirred at room temperature for. 3 h. The reactionwas quenched by the addition of NaHCO₃ (15 mL, sat. aq.) and extractedwith EtOAc (3×25 mL). The combined extracts were dried over Na₂SO₄ andconcentrated in vacuo to give 106 as a white solid (83 mg, 75% yield).

[0629]¹H NMR (500 MHz, CD₃OD) δ0.80 (t, 3H, J=7.1 Hz), 0.92 (d, 3H,J=6.7 Hz), 1.15-1.25 (m, 26H), 1.30-1.40 (m, 2H), 2.19 (s, 6H),2.30-2.35 (m, 1H), 3.60-3.65 (m, 1H);

[0630]¹³C NMR (125 MHz, CD₃OD) δ8.7, 14.9, 24.2, 27.7, 30.9, 31.2, 33.5,36.8, 42.2, 65.0, 73.3;

[0631] ESMS calcd for C₂₀H₄₄NO (M+H) 314.3, found 314.4.

EXAMPLE 105

[0632] (4S,5R)-4-Methyl-5-(n-pentadecyl)-1,3-oxazolidinone, 107.

[0633] A mixture of aminoalcohol 1 (150 mg, 0.53 mmol) and carbonyldiimidazole (94 mg, 0.58 mmol) in THF (10 mL) was stirred at 60° C. for3 h. Then, the solvent was removed in vacuo and the residue wasdissolved in CH₂Cl₂ (40 mL), washed successively with HCl (2N, 40 mL),H₂O (40 mL) and brine (40 mL), dried over Na₂SO₄ and concentrated invacuo to give oxazolidinone 107 as a white solid (160 mg, 98% yield).

[0634] R_(f) 0.21 (hexane/EtOAc 2:1);

[0635]¹H NMR (300 MHz, CD₃OD) δ0.80 (t, 3H, J=7.0 Hz), 1.02 (d, 3H,J=6.5 Hz), 1.15-1.30,(m, 26H), 1.40-1.55 (m, 2H), 3.81 (quint, 1H, J=6.5Hz), 4.44-4.52 (m, 1H);

[0636]¹³C NMR (75 MHz, CDCl₃) δ14.1, 20.7, 22.7, 24.8, 29.3, 29.4, 29.4,29.5, 29.7, 31.9, 34.1, 53.5, 84.2, 158.7;

[0637] ESMS calcd for C₁₉H₃₇NO₂Na (M+Na) 334.3, found 334.3.

EXAMPLE 106

[0638] (2S,3R)-2-(N-Methylamino)-3-octadecanol, 108.

[0639] To a cold (0° C.) solution of 107 (160 mg, 0.52 mmol) in THF(20mL), LiAlH₄ (1M in THF, 1.04 mL, 1.04 mmol), was added dropwise. Themixture was stirred overnight at room temperature. A further portion ofLiAlH₄ (1.04 mL, 1.04 mmol) was added and the reaction left for 2 moredays. The reaction was quenched with H₂O containing a few drops of NH₄OH(20 mL) and extracted with EtOAc (3×20 mL). The combined extracts weresuccessively washed with. H₂O (30 mL) and brine (30 mL), dried overNa₂SO₄ and concentrated in vacuo. The crude was purified by columnchromatography on silica (50% to 75% CH₂Cl₂/hexane to 100% CH₂Cl₂ to 10%MeOH/CHCl₃ and a few drops of NH₄OH) to give 108 as a white solid (35mg, 23% yield).

[0640]¹H NMR (500 MHz, CD₃OD) δ0.80 (t, 3H, J=7.1 Hz), 0.92 (d, 3H,J=6.7 Hz), 1.15-1.25 (m, 26H), 1.30-1.45 (m, 2H), 2.19 (s, 3H),2.50-2.55 (m, 1H), 3.55-3.60 (m, 1H);

[0641]¹³C NMR (125 MHz, CD₃OD) δ13.3, 14.9, 24.2, 27.8, 30.9, 31.2,33.5, 34.7, 36.8, 42.3, 60.5, 73.1;

[0642] ESMS calcd for C₁₉H₄₂NO (M+H) 300.3, found 300.3.

EXAMPLE 107

[0643] (2S,3R)-2-Amino-N-(phenylthiocarbamoyl)-3-octadecanol, 109.

[0644] To a solution of aminoalcohol 1 (197 mg, 0.69 mmol) in THP (3.5mL) at room temperature, PhNCS (0.165 mL, 1.38 mmol) was added. Thereaction was stirred for 1 h, and then the solvents were evaporated invacuo. The crude was purified by column chromatography on silica(hexane/EtOAc 5:1 to 2:1) to give phenylthiourea 109 as a white solid(246 mg, 85% yield).

[0645] R_(f) 0.29 (exane/EtOAc 2:1);

[0646]¹H NMR (300 MHz, CDCl₃) δ0.85 (t, 3H, J=6.7 Hz), 1.08 (d, 3H,J=6.9 Hz), 1.20-1.30 (m, 26H), 1.35-1.45 (m, 2H), 2.20 (br s, 1H),3.72-3.82 (m, 1H) 4.45-4.60 (m, 1H), 6.58 (d, 1H, J=8.6 Hz), 7.18-7.38(m, 5H), 8.39 (br s, 1H);

[0647]¹³C NMR (75 MHz, CDCl₃) δ12.9, 14.0, 22.6, 25.8, 29.2, 29.4, 29.5,29.5, 29.6, 31.8, 33.7, 54.5, 73.5, 124.4, 126.6, 129.9, 136.4, 179.0;

[0648] ESMS calcd for C₂₅H₄₃N₂OS (M−H) 419.3, found 419.2.

EXAMPLE 108

[0649] (2S,3R)-2-Amino-N-(phenylcarbamoyl)-3-octadecanol, 110.

[0650] According to the method of Example 107, from aminoalcohol 1 (23mg, 0.08 mmol) and PhNCO (18 μL, 0.16. mmol), phenylurea 110 wasobtained as a white solid (15 mg, 46% yield).

[0651] R_(f) 0.50 (hexane/EtOAc 5:1);

[0652]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.7 Hz), 1.11 (d, 3H,J=6.9 Hz), 1.20-1.30 (m, 26H), 1.35-1.45 (m, 2H), 2.17 (br s, 1H),3.63-3.73 (m, 1H) 3.90-4.06 (m, 1H), 5.02 (d, 1H, J=7.2 Hz), 6.58 (br s,1H), 7.05-7.12 (m, 1H), 7.25-7.34 (m, 4H);

[0653] ESMS calcd for C₂₅H₄₅N₂O₂ (M+H) 405.3, found 405.4.

EXAMPLE 109

[0654] (2S,3R)-2-Amino-N-(n-butylcarbamoyl)-3-octadecanol, 111.

[0655] According to the method of Example 107, from aminoalcohol 1 (27mg, 0.09 mmol) and n-BuNCO (21 μL, 0.19 mmol), n-butylurea 111 wasobtained as a white solid (13 mg, 36% yield).

[0656] R_(f) 0.25 (hexane/EtOAc 2:1);

[0657]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.9 Hz), 0.92.(t, 3H,J=7.2 Hz), 1.08 (d, 3H, J=6.9 Hz), 1.20-1.40 (m, 28H), 1.40-1.55 (m,4H), 2.91 (br s, 1H), 3.14 (q, 2H, J=6.5 Hz), 3.61 (br s, 1H), 3.78-3.88(m, 1H), 4.56-4.66 (m, 2H);

[0658] ESMS calcd for C₂₃H₄₉N₂O₂ (M+H) 385.4, found 385.4.

EXAMPLE 110

[0659] (2S,3R)-2-(Methanesulfonamide)-3-octadecanoI, 112.

[0660] To a solution of aminoalcohol 1 (40 mg, 0.14 mmol) in CH₂Cl₂ (5.0mL) at room temperature, ClSO₂Me (11 μL, 0.14 mmol) was added. Afterstirring for 1 h, the reaction was quenched with H₂O (10 mL), extractedwith CH₂Cl₂ (3×10 mL), dried over Na₂SO₄ and concentrated in vacuo. Thecrude was purified by column chromatography on silica (hexane/EtOAc 4:1)to obtain sulfonamide 112 as a white solid (49 mg, 96% yield).

[0661] R_(f) 0.13 (hexane/EtOAc 4:1);

[0662]¹H NMR (300 MHz, CD₃OD) δ0.85 (t, 3H, J=6.8 Hz), 1.19 (t, 3H J=6.8Hz), 1.20-1.40 (m, 26H), 1.47-1.53 (m, 2H), 1.86 (d, 1H,. J=5.1 Hz),3.00 (s, 3H), 3.53 (t, 1H, J=6.1 Hz), 3.66-3.72 (m, 1H), 4.66 (d, 1H,J=8.1 Hz);

[0663]¹³C NMR (75 MHz, CDCl₃) δ12.0, 14.5, 16.4, 23.2, 26.9, 27.2, 30.6,30.7, 30.8, 33.1, 34.2, 41.6, 55.3, 71.5;

[0664] ESMS calcd for C₁₈H₃₈NO (M−SO₂Me) 286.2, found 286.5.

EXAMPLE 111

[0665] (2S,3R)-2-(Methanesulfonamide)-3-nonadecanol, 113

[0666] According to the method of Example 110, from aminoalcohol 2 (25mg, 0.08 mmol), sulfonamide 113 was obtained as a white solid (29 mg,94% yield).

[0667]¹H NMR (300 MHz, CD₃OD) δ0.87 (t, 3H, J=6.4 Hz), 1.17 (d, 3H,J=6.4 Hz), 1.20-1.40 (m, 28H), 1.46-1.53 (m, 2H), 1.98-2.05 (m, 1H),2.97-3.03 (m, 1H), 3.47-3.58 (m, 1H), 3.68-3.74 (m, 1H), 4.77-4.83 (m,1H);

[0668]¹³C NMR (75 MHz, CDCl₃) δ14.3, 15.5, 22.9, 26.2, 29.5, 29.7, 29.8,29.9, 32.1, 33.4, 42.0, 54.0, 74.6;

[0669] ESMS calcd for C₁₉H₄₀NO (M−SO2Me) 300.3, found 300.3.

EXAMPLE 112

[0670] (2S,3R)-2-(2,2,2-Trifluoroacetylamino)-3-octadecanol, 114, and(2S,3R)-2-(21,2,2-trifluoroacetylamino)-b(2,2,2-trifluoroacetyl)-octadecanol,115.

[0671] To a solution of aminoalcohol 1 (27 mg, 0.09 mmol) in CH₂Cl₂ (5.0mL) at room temperature, trifluoroacetic anhydride (12.8 μL, 0.09 mmol)was added. After stirring for 1 h, the solvents were removed in vacuo.The crude was purified by column chromatography on silica (hexane/CH₂Cl₂1:1) to obtain 114 (9 mg, 25% yield) R_(f) 0.34 (hexane/CH₂Cl₂ 1:1) and115 (11 mg, 24% yield) R_(f) 0.52 (hexane/CH₂Cl₂ 1:1) as white solids.

[0672] 114: ¹H NMR (300 MHz, CD₃OD) & 0.85 (t, 3H, J=6.9 Hz), 1.05 (d,3H, J=7.0 Hz), 1.19-1.38 (m, 26H), 1.45-1.53 (m, 2H), 3.60-3.66 (m, 1H),3.93-3.98 (m, 1H), 6.65 (d, 1H, J=7.5Hz);

[0673]¹³C NMR (75 MHz, CDCl₃) δ12.9, 14.3, 15.4, 22.9, 25.9, 29.5, 29.7,29.8, 31,8, 32.1, 34.2, 49.6, 73.2, 76.8, 114.4, 118.2, 121.8, 151.4,156.9;

[0674] ESMS calcd for C₂₀H₃₈F₃NO₂Na (M+Na) 404.3, found 404.8.

[0675] 115: ¹H NMR (300 MHz. CD₃OD) δ0.89 (t, 3H, J=7.6 Hz), 1.20-1.39(m, 26H), 2.46-2.55 (m, 2H), 4.01-4.43 (m,1H), 4.95-5.24 (m, 1H),6.00-6.34 (m, 1H).

EXAMPLE 113

[0676] (2S,3R)-2-(2,2,2-Trifluoroacetylamino)-3-nonadecanol, 116, and(2S,3R)-2-(2,2,2-trifluoroacetylamino)-O-(2,2,2-trifluoroacetyl)-nonadecanol,117.

[0677] According to the method of Example 112, from aminoalcohol 2 (22mg, 0.07 mmol), 116 (6 mg, 22% yield) and 117 (8 mg, 23% yield) wereobtained as white solids.

[0678] 116: ¹H NMR (300 MHz, CD₃OD) δ0.85 (t, 3H, J=6.8 Hz), 1.01 (d,3H, J=6.8Hz), 1.23-1.41 (m, 28H), 1.45-1.53 (m, 2H), 3.65-3.73 (m, 1H),3.96-4.06 (m, 1H), 6.68-6.73 (m, 1H).

[0679] 117: ¹H NMR (300 MHz, CD₃OD) δ0.88 (t, 3H, J=7.6 Hz,), 1.25-1.38(m, 26H), 2.47-2.60 (m, 2H), 4.00-4.40 (m, 1H), 4.97-5.28 (m, 1H),6.01-6.35 (m, 1H).

EXAMPLE 114

[0680] (2S,3R)-2-Amino-N-(trans-cinnamoyl)-3- octadecanol, 118.

[0681] To a solution of aminoalcohol 1 (30 mg, 0.10 mmol) in CH₂Cl₂ (3.0mL) at room temperature, pyridine (58 mL, 0.11 mmol) and cinnamoylchloride (16.6 mg, 0.36 mmol) were added. After stirring for 1 h, thereaction was quenched with H₂O (10 mL), extracted with CH₂Cl₂ (3×10 mL),dried over Na₂SO₄ and concentrated in vacuo. The crude was purified bycolumn chromatography on silica (hexane/EtOAc 4:1) to obtain 118 as awhite solid (32 mg, 74% yield).

[0682] R_(f) 0.31(hexane/EtOAc 2:1);

[0683]¹H NMR (300 MHz, CD₃OD) δ0.87 (t, 3H, J=6.9 Hz), 1.16 (d, 3H,J=6.9 Hz), 1.21-1.40 (m, 26H), 1.33-1.40 (m, 2H), 2.28-2.35 (m, 1H),3.64-3.71 (m, 1H), 4.06-4.18 (m, 1H), 5.92 (d, 1H, J=15.6 Hz), 6.40 (d,1H, J=15.6 Hz), 7.31-7.36 (m, 3H), 7.41-7.50 (m, 2H), 7.62 (d, 1H,J=15.6 Hz);

[0684]¹³C NMR (75 MHz, CDCl3) δ14.9, 25.3, 26.2, 29.5, 29.9, 33.8, 49.9,74.3, 124.2, 126.8, 129.8, 130.9, 136.1, 165.1;

[0685] ESMS calcd for C₂₇H₄₅NO₂Na (M+Na) 438.3, found 438.3.

EXAMPLE 115

[0686](2S,3R)-2-Amino-N-[trans-3-(trifluoromethyl)-cinnamoyl]-3-octadecanol,119.

[0687] According to the method of Example 114, from aminoalcohol 1 (30mg, 0.10 mmol) and 3-(trifluoromethyl)-cinnamoyl chloride (24.6 mg, 0.10mmol), amide 119 was obtained as a white solid (28 mg, 56% yield).

[0688] R_(f) 0.30 (hexane/EtOAc 2:1);

[0689]¹H NMR (300 MHz, CD₃OD) δ0.87 (t, 3H, J=6.9 Hz), 1.16 (d, 3H,J=6.9 Hz), 1.20-1.40 (m, 26H), 1.35-1.41 (m, 2H), 3.68-3.74 (m, 1H),3.98-4.20 (m, 1H), 6.06 (d, 1H, J=9.6 Hz), 6.45 (d, J=6.9 Hz, 1H),7.48-7.78 (m, 4H);

[0690]¹³C NMR (75 MHz, CDCl₃) δ14.1, 22.9 26.2, 29.6, 29.8, 29.9, 32.1,33.9, 49.9, 74.4, 122.8, 124.1, 124.2, 126.3, 129.5, 131.3, 135.8,139.7, 165.2;

[0691] ESMS calcd for C₂₈H₄₄F₃NO₂Na (M+Na) 506.3, found 506.4.

EXAMPLE 116

[0692] (2S,3R)-2-Amino-N-(palmitoyl)-3-octadecanol, 120.

[0693] To a solution of aminoalcohol 1 (30 mg, 0.10 mmol) in CH₂Cl₂ (3.0mL) at room temperature, palmitic acid (28 mg, 0.11 mmol), EDC (50.2 mg,0.26 mmol), DIPEA (39 μL, 0.15 mmol) and DMAP (1.2 mg, 0.01 mmol) wereadded. After stirring for 2 h, the reaction was quenched with H₂O (10mL), extracted with CH₂Cl₂ (3×10 mL), dried over Na₂SO₄ and concentratedin vacuo. The crude was purified by column chromatography on silica(hexane/EtOAc 4:1) to obtain 120 as a white solid (48 mg, 87% yield).

[0694] R_(f) 0.21 (hexane/EtOAc 4:1);

[0695]¹H NMR (300 MHz, CD₃OD) δ0.85-0.94 (m, 6H), 1.08 (d, 3H, J=7.1Hz), 1.20-1.40 (m, 52H), 1.58-1.65 (m, 2H) 2.16 (t, 2H, .J=7.1Hz),2.29-2.33 (m, 1H), 3.58-3.64 (m, 1H), 3.93-4.13 (m, 1H), 5.72 (d, 1H,J=7.1 Hz);

[0696]¹³C NMR (75 MHz, CDCl₃) δ14.1, 15.2, 22.7, 25.8, 25.9, 29.2, 29.3,29.5, 29.6, 29.7, 31.9, 33.5, 36.9, 49.4, 65.8, 74.4, 173.1;

[0697] ESMS calcd for C₃₄H₆₉NO₂Na (M+Na) 546.5, found 546.8.

EXAMPLE 117

[0698] (2S,3R)-2-[2-(tert-Butoxycarbonylaminio)-3-methylbutyramide)]-3-octadecanol,121.

[0699] To a solution of aminoalcohol 1 (30 mg, 0.10 mmol) in CH₂C1₂ (3.0mL) at room temperature, N-Boc-valine (23 mg, 0.11 mmol), EDC (50.2 mg,0.26 mmol), DIPEA (39 μL, 0.15 mmol) and DMAP (1.2 mg, 0.01 mmol) wereadded. After stirring for 2 h, the reaction was quenched with H₂O (10mL), extracted with CH₂Cl₂ (3×10 mL), dried over Na₂SO₄ and concentratedin vacuo. The crude was purified by column chromatography on silica(hexane/EtOAc 4:1) to obtain 121 as a white solid (48 mg, 87% yield).

[0700] R_(f) 0.13 (hexane/EtOAc 4:1′);

[0701]¹H NMR (300 MHz, CD₃OD) δ0.86 (t, 3H, J=6.9 Hz), 0.91 (d, 3H,J=6.9 Hz), 0.96 (d, 3H, J=6.9 Hz), 1.08 (d, 3H, J=6.9 Hz), 1.20-1.40 (m,26H), 1.38-1.46 (m, 11H), 1.99-2.23 (m, 1H), 2.33-2.78 (m, 1H), 3.64 (m,1H), 3.83 (t, 1H, J=6.3 Hz), 3.98 (m, 1H), 5.06 (d, 1H, J=6.8 Hz), 6.29(d, 1H, J=7.8 Hz);

[0702]¹³C NMR (75 MHz, CDCl₃) δ13.7, 14.1, 17.8, 19.3, 22.7,.26.0, 28.3,29.3, 29.5, 29.7, 30.6, 31.9, 33.5, 49.6, 60.4, 73.8, 157.4, 171.3;

[0703] ESMS calcd for C₂₈H₅₇N₂O₄ (M+Ha) 485.4, found 485.7.

EXAMPLE 118

[0704] (2S,3R)-2-[2-Amino-3-methylbutyramide)]-3-octadecanolhydrochloride, 122.

[0705] According to the method of Example 95, from N-Boc derivative 121(24 mg, 0.05 mmol), hydrochloride 122 was obtained as a white solid (15mg, 75% yield).

[0706]¹H NMR (300 MHz, CD₃OD) δ0.87 (t, 3H, J=6.8 Hz), 1.07-1.11 (m,6H), 1.13 (d, 3H, J=6.8 Hz), 1.21-1.40 (m, 26H), 1.41-1.52 (m, 2H),2.09-2.11 (m, 1H), 3.40-3.47 (m, 1H), 3.66-3.77 (m, 1H), 3.87-3.93 (m,1H);

[0707]¹³C NMR (75 MHz, CDCl₃) δ12.7, 13.1, 16.7, 17.8, 18.3, 21.6, 25.2,27.2, 28.3, 28.7, 29.6, 30.9, 32.3, 49.6, 66.0,. 72.5, 166.7;

[0708] ESMS calcd for C₂₃H₄₉N₂O₂ (M−Cl) 385.3, found 385.3.

EXAMPLE 119

[0709] (2S)-2-(N-tert-Butoxycarbonylamino)-3-heptadecanone, 123.

[0710] To a solution of aminoalcohol 37 (82 mg, 0.274 mmol) in dioxane(0.7 mL) and H₂O (0.4 mL) at room temperature, NaOH (1M, aq., 0.3 mL)was added followed by Boc2O (66 mg, 0.301 mmol). After stirring for 2 h,the reaction was diluted with EtOAc (10 mL) and KHSO₄ (10% aq., 10 mL)was added. The layers were separated and the aqueous layer extractedwith EtOAc (3×10 mL). The organic layers were dried over Na₂SO₄ andconcentrated in vacuo to obtain the crude N-Boc derivative as a whitesolid. To a cold (−78° C.) solution of (COCl)₂ (2M in CH₂Cl₂, 0.22 mL,0.447 mmol) in CH₂Cl₂ (4.5 mL), DMSO (0.063 mL, 0.894 mmol) was addeddropwise. After stirring at −78° C. for 15 min, a solution of the N-Bocderivative (69 mg, 0.179 mmol) in CH₂Cl₂ (2 mL) was added dropwise. Themixture was stirred at −78° C. for 1 h, and then Et₃N (0.187 mL, 1.34mmol) was added. The reaction was warmed up to 0° C. and stirred for 15min, followed by the addition of NH₄Cl (15 mL, sat. aq.). The crude wasextracted with CH₂Cl₂ (3×15 mL), washed successively with NaHCO₃ (30 mL,sat. aq.) and brine (30 mL), dried over Na₂SO₄ and concentrated invacuo. The crude was purified by column chromatography on silica(hexane/EtOAc 5:1) to obtain ketone 123 as a white solid (40 mg, 56%yield) together with unreacted starting material (30 mg). R_(f) 0.42(hexane/EtOAc 5:1);

[0711]¹H NMR (300 MHz, CDCl₃) δ0.85 (t, 3H, J=6.4 Hz), 1.20-1.37 (m,25H), 1.42 (s, 9H), 1.54-1.62 (m, 2H), 2.38-2.56 (m, 2H), 4.29 (quint,1H, J=6.5 Hz), 5.28 (br d, 1H, J=5.2 Hz);

[0712]¹³C NMR (75 MHz, CDCl₃) δ14.0, 17.9, 22.6, 23.5, 28.3, 29.2, 29.3,29.4, 29.5, 29.6, 31.9, 39.1, 55.0, 209.7;

[0713] ESMS calcd for C₂₂H₄₃NO₃Na (M+Na) 392.3, found 392.3.

EXAMPLE 120

[0714] (2S)-2-Amino-3-heptadecanone hydrochloride, 124.

[0715] According to the method of Example 95, from ketone 123 (33.5 mg,0.091 mmol), hydrochloride 124 was obtained as a white solid (22 mg, 79%yield).

[0716]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.9 Hz),. 1.20-1.35 (m,22H), 1.51 (d, 3H, J=7.4 Hz), 1.55-1.65. (m, 2H), 2.50-2.72 (m, 2H),4.13 (q, 1H, J=7.4 Hz);

[0717]¹³C NMR (75 MHz, CD₃OD) δ14.4, 15.7, 23.7, 24.3, 30.1, 30.5, 30.5,30.6, 30.7, 30.8, 33.1, 39.2, 55.8, 207.4;

[0718] ESMS calcd for C₁₇H₃₆NO (M−Cl) 270.3, found 270.2.

EXAMPLE 121

[0719] (2S)-2-(N-tert-Butoxycarbonylamino)-3-octadecanone, 125.

[0720] According to the method of Example 119, from aminoalcohol 1 (53mg, 0.186 mmol), ketone 125 was obtained as a white solid (27 mg, 38%yield), together with unreacted starting alcohol (24 mg). R_(f) 0.42(hexane/EtOAc 5:1);

[0721]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.4 Hz), 1.20-1.37 (m,27H), 1.43 (s, 9H), 1.54-1.62 (m, 2H), 2.38-2.56 (m, 2H), 4.30 (quint,1H, J=6.8 Hz), 5.27. (br s, 1H);

[0722]¹³C NMR (75 MHz, CDCl₃) δ14.1, 17.9, 22.7, 23.6, 28.3, 29.2, 29.3,29.4, 29.6, 29.7, 31.9, 39.2, 55.0, 209.7;

[0723] ESMS calcd for C₂₃H₄₅NO₃Na (M+Na) 406.3, found 406.3.

EXAMPLE 122

[0724] (2S)-2-Amino-3-octadecanone hydrochloride, 126.

[0725] According to the method of Example 95, from ketone 125 (24 mg,0.063 mmol), hydrochloride 126 was obtained as a white solid (17 mg, 85%yield).

[0726]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.9 Hz), 1.20-1.35 (m,24H), 1.51 (d, 3H, J=7.4 Hz), 1.55-1.65 (m, 2H), 2.50-2.72 (m, 2H), 4.13(q, 1H, J=7.4 Hz);

[0727]¹³C NMR (75 MHz, CD₃OD) δ14.4, 15.7, 23.7, 24.3, 30.1, 30.5, 30.5,30.6, 30.8, 33.1, 39.2, 55.8, 207.4;

[0728] ESMS calcd for C₁₈H₃₈NO (M−Cl) 284.3, found 284.3.

EXAMPLE 123

[0729] (2S)-2-Amino-3-octadecanone oxime, 127.

[0730] To a solution of ketone 126 (108 mg, 0.34 mmol) in 2.5 mL ofEtOH, NH₂OH.HCl (117 mg, 1.69 mmol) and AcONa (249 mg, 3.04 mmol) wereadded. The mixture was stirred at 80° C. for 8 h, and then the solventwas evaporated in vacuo. The residue was suspended in H₂O, filtered andwashed with H₂O. The collected solid was recystallised from EtOAc toobtain oxime 127 as a white solid (70 mg, 69% yield).

[0731]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.7 Hz), 1.20-1.35 (m,27H), 1.55-1.65 (m, 2H), 2.18 (ddd, 1H, J=12.9, 10.1, 6.0 Hz), 2.47(ddd, 1H, J=12.9, 9.6, 6.4 Hz), 3.72 (q, 1H, J=6.7 Hz);

[0732]¹³C NMR (75 MHz, CD₃OD) δ14.5, 18.3, 23.7, 24.0, 26.6, 26.7, 30.4,30.5,30.7, 30.8, 31.0, 33.1, 50.2, 158.0;

[0733] ESMS calcd for C₁₈H₃₉N₂O (M+H) 299.3, found 299.3.

EXAMPLE 124

[0734] (2S)-2-(N-tert-Butoxycarbonylamino)-3-nonadecanone, 128.

[0735] According to the method of Example 119, from aminoalcohol 2 (59mg, 0.197 mmol), ketone 128 was obtained as a white solid (44 mg, 56%yield).

[0736] R_(f) 0.42 (hexane/EtOAc 5:1);

[0737]¹H NMR (300 MHz, CDCl₃) δ0.85 (t, 3H, J=6.4 Hz), 1.20-1.37 (m,29H), 1.42 (s, 9H), 1.54-1.62 (m, 2H), 2.38-2.56 (m, 2H), 4.28 (quint,1H, J=6.7 Hz), 5.29 (br d, 1H, J=6.2 Hz);

[0738]¹³C NMR (75 MHz, CDCl₃) δ14.0, 17.8, 22.6, 23.5, 28.3, 29.2, 29.3,29.4, 29.5, 29.6, 31.9, 39.1, 55.0, 209.7;

[0739] ESMS calcd for C₂₄H₄₇NO₃Na (M+Na) 420.4, found 420.2.

EXAMPLE 125

[0740] (2S)-2-Amino-3-nonadecanone hydrochloride, 129.

[0741] According to the method of Example 95, from ketone 128 (33 mg,0.083 mmol), hydrochloride 129 was obtained as a white solid (25 mg, 90%yield).

[0742]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.9 Hz), 1.20-1.35 (m,26H), 1.51 (d, 3H, J=7.4 Hz), 1.55-1.65 (m, 2H), 2.50-2.72 (m, 2H), 4.13(q, 1H, J=7.4 Hz);

[0743]¹³C NMR (75 MHz, CD₃OD) δ14.4, 15.7, 23.7, 24.3, 30.1, 30.5, 30.5,30.6, 30.8, 33.1, 39.2, 55.8, 207.4;

[0744] ESMS calcd for C₁₉H₄₀NO (M−Cl) 298.3, found 298.3.

EXAMPLE 126

[0745] (2S)-2-(N-tert-Butoxycarbonylamin)-3-eicosadecanone, 130.

[0746] According to the method of Example 119, from aminoalcohol 3 (81mg, 0.258 mmol), ketone 130 was obtained as a white solid (75 mg, 70%yield).

[0747] R_(f) 0.42 (hexane/EtOAc 5:1);

[0748]¹H NMR (300 MHz, CDCl₃) δ0.86 (t, 3H, J=6.2 Hz), .1.20-1.37 (m,31H), 1.42 (s, 9H), 1.54-1.62 (m, 2H), 2.38-2.56 (m, 2H), 4.29 (quint,1H, J=6.5 Hz), 5.29 (br d, 1H, J=5.4 Hz);

[0749]¹³C NMR (75 MHz, CDCl₃) δ14.0, 17.8, 22.6, 23.5, 28.3, 29.2, 29.3,29.4, 29.5, 29.6, 31.9, 39.1, 55.0, 209.6;

[0750] ESMS calcd for C₂₅H₄₉NO₃Na (M+Na) 434.4, found 434.3.

EXAMPLE 127

[0751] (2 S)-2-Amino-3-eicosadecanone hydrochloride, 131.

[0752] According to the method of Example 95, from ketone 130 (47 mg,0.114 mmol), hydrochloride 131 was obtained as a white solid (30.5 mg,77% yield).

[0753]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.9 Hz), 1.20-1.35 (m,28H), 1.50 (d, 3H, J=7.2 Hz), 1.55-1.65 (m, 2H), 2.50-2.72 (m, 2H), 4.13(q, 1H, J=7.2 Hz);

[0754]¹³C NMR (75 MHz, CD₃OD) δ14.4, 15.7, 23.7, 24.3, 30.1, 30.5, 30.5,30.6, 30.7, 30.8, 33.1, 39.2, 55.8, 207.4;

[0755] ESMS calcd for C₂₀H₄₂NO (M−Cl) 312.3, found 312.3.

EXAMPLE 128

[0756] (3S)-3-(N-tert-Butoxycarbonylamino)-4-nonadecanone, 132.

[0757] According to the method of Example 119, from aminoalcohol 57 (82mg, 0.274 mmol), ketone 132 was obtained as a white solid (54 mg, 50%yield).

[0758] R_(f) 0.42 (hexane/EtOAc 5:1);

[0759]¹H NMR (300 MHz, CDCl₃) δ0.86 (t, 6H, J=7.0 Hz), 1.20-1.35 (m,24H), 1.43 (s, 9H), 1.55-1.65 (m, 3H), 1.84-1.96 (m, 1H), 2.38-2.56 (m,2H), 4.28 (q, 1H, J=5.5 Hz), 5.24 (br d, 1H, J=6.9 Hz);

[0760]¹³C NMR (75 MHz, CDCl₃) δ9.2, 14.0, 22.6, 23.5, 24.8, 28.3, 29.2,29.3, 29.4, 29.6, 29.6, 31.9, 39.8, 60.1, 209.4;

[0761] ESMS calcd for C₂₄H₄₇NO₃Na (M+Na) 420.4, found 420.3.

EXAMPLE 129

[0762] (3S)-3-Amino-4-nonadecanone hydrochloride, 133.

[0763] According to the method of Example 95, from ketone 132 (36.5 mg,0.092 mmol),. hydrochloride 133 was obtained as a white solid (29 mg,95% yield).

[0764]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.7 Hz), 1.00 (t, 3H,J=7.5 Hz), 1.20-1.35 (m, 24H), 1.55-1.65 (m, 2H), 1.82-1.96 (m, 1H),2.00-2.12 (m, 1H), 2.50-2.72 (m, 2H), 4.11 (dd, 1H, J=7.2, 4.5 Hz);

[0765]¹³C NMR (75 MHz, CD₃OD) δ9.3, 14.5, 23.8, 23.9, 24.3, 30.1, 30.5,30.5, 30.6, 30.7, 30.8, 33.1, 39.8, 61.0, 207.1;

[0766] ESMS calcd for C₁₉H₄₀NO (M−Cl) 298.3, found 298.3.

EXAMPLE 130

[0767] (2R)-2-(N-tert-Butoxycarbonylamino)-3-octadecanone, 134.

[0768] According to the method of Example 119, from aminoalcohol 81 (53mg, 0.186 mmol), ketone 134 was obtained as a white solid (40 mg, 56%yield).

[0769] R_(f) 0.42 (hexane/EtOAc 5:1);

[0770]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.4 Hz), 1.20-1.37 (m,27H), 1.43 (s, 9H), 1.54-1.62 (m, 2H), 2.38-2.56 (m, 2H), 4.30 (quint,1H, J=6.8 Hz), 5.27 (br s, 1H);

[0771]¹³C NMR (75 MHz, CDCl₃) δ14.1, 17.9,.22.7, 23.6, 28.3, 29.2, 29.3,29.4, 29.6, 29.7, 31.9, 39.2, 55.0, 209.7;

[0772] ESMS calcd for C₂₃H₄₅NO₃Na (M+Na) 406.3, found 406.2.

EXAMPLE 131

[0773] (2R)-2-Amino-3-octadecanone hydrochloride, 135.

[0774] According to the method of Example 95, from ketone 134 (30 mg,0.078 mmol), hydrochloride 135 was obtained as a white solid (24 mg, 96%yield).

[0775]¹H NMR (300 MHz, CD₃OD) δ0.89 (t, 3H, J=6.9 Hz), 1.20-1.35 (m,24H), 1.51 (d, 3H, J=7.4 Hz), 1.55-1.65 (m, 2H), 2.50-2.72 (m, 2H), 4.13(q, 1H, J=7.4 Hz);

[0776]¹³C NMR (75 MHz, CD₃OD) δ14.4, 15.7, 23.7, 24.3, 30.1, 30.5, 30.5,30.6, 30.8, 33.1, 39.2, 55.8, 207.4;

[0777] ESMS calcd for C₁₈H₃₈NO (M−Cl) 284.3, found 284.2.

EXAMPLE 132

[0778] (2S,3R)-2-Amino-1-(tert-butyldiphenylsilyloxy)-octadec4-en-3-ol,136.

[0779] To a solution of D-erythro-sphingosine (46 mg, 0.153 mmol) inCH₂Cl₂ (1.5 mL) at room temperature, Et₃N (32 μL, 0.230 mmol), TBDPSCl(44 μL, 0.169 mmol) and 4-DMAP (ca. 5 mg, cat.) were added. Afterstirring for 4 h, the reaction was quenched with H₂O (10 mL), extractedwith EtOAc (3×10 mL), dried over Na₂SO₄ and concentrated in vacuo. Thecrude was purified by column chromatography on silica (hexane/EtOAc 5:1to 100% EtOAc) to obtain 136 as a colorless oil (33 mg, 40% yield).

[0780] R_(f) 0.20 (hexane/EtOAc 1:5);

[0781]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=6.9 Hz), 1.06 (s, 9H),1.20-1.40 (m, 22H), 1.91 (br s, 3H), 2.01 (q, 2H, J=6.5 Hz), 2.93 (q,1H, J=5.5 Hz), 3.69 (d, 2H, J=4.5 Hz), 4.09 (t, 1H, J=6.1 Hz), 5.40 (dd,1H, J=15.3, 6.9 Hz), 5.73 (dt, 1H, J=15.4, 6.5 Hz), 7.35-7.46 (m, 6H),7.64-7.68 (m, 4H);

[0782]¹³C NMR (75 MHz, CDCl₃) δ14.1, 19.2, 22.7, 26.8, 29.2, 29.2, 29.3,29.5, 29.6, 29.7, 31.9, 32.3, 56.3, 66.2, 74.6, 127.7, 128.9, 129.8,133.1, 134.1, 135.5;

[0783] ESMS calcd for C₃₄H₅₆NO₂Si (M+H) 538.4, found 538.4.

EXAMPLE 133

[0784](4S,5R)-4-(tert-Butyldimethylsilyloxymethyl)-5-(n-pentadec-2′-enyl)-1,3-oxazolidinone,137.

[0785] According to the method of Example 105, from aminoalcohol 136 (33mg, 0.061 mmol), oxazolidinone 137 was obtained as a colorless oil (32mg, 92% yield).

[0786] R_(f) 0.60 hexane/EtOAc 1:1);

[0787]¹H NMR (300 MHz, CDCl₃) δ0.86 (t, 3H, J=7.0 Hz), 1.06 (s. 9H),1.20-1.40 (m, 22H), 2.00 (q, 2H, J=6.9 Hz), 3.58 (dd, 1H, J=10.6, 4.7Hz), 3.64 (dd, 1H, J=10.6, 6.7 Hz), 3.82-3.88 (m, 1H), 5.02 (t, 1H,J=8.1 Hz), 5.32 (br s, 1H), 5.51 (dd, 1H, J=15.4, 8.1 Hz), 5.83 (dt, 1H,J=15.4, 6.5 Hz), 7.37-7.46 (m, 6H), 7.61-7.65 (m, 4H);

[0788]¹³C NMR (75 MHz, CDCl₃) δ14.1, 19.1, 22.7, 26.7, 28.7, 29.1, 29.3,29.4, 29.5, 29.6, 31.9, 32.1, 57.2, 63.1, 79.4, 122.1, 127.9,, 130.0,132.7, 135.5, 138.4, 158.9;

[0789] ESMS calcd for C₃₅H₅₃NO₃SiNa (M+Na) 586.4, found 586.5.

EXAMPLE 134

[0790](4S,5R)-4-(Hydroxymethyl)-5-(n-pentadec-2′-enyl)-1,3-oxazolidinone, 138.

[0791] To a solution of 137 (32 mg, 0.057 mmol) in THF (0.6 mL) at roomtemperature, TBAF (1M in THF, 113 μL, 0.113 mmol) was added. Afterstirring for 30 min, the reaction was quenched with H₂O (10 mL),extracted with EtOAc (3×10 mL), dried over Na₂SO₄ and concentrated invacuo. The crude was purified by column chromatography on silica(hexane/EtOAc 1:1 to 1:5) to obtain alcohol 138 as a white solid (13 mg,70% yield).

[0792] R_(f) 0.27 (hexane/EtOAc 1:5);

[0793]¹H NMR (300 MHz, CD₃OD) δ0.90 (t, 3H, J=6.7 Hz), 1.25-1.50 (m,22H), 2.12 (q, 2H, J=6.9 Hz), 3.51 (dd, 1H, J=11.6, 5.9 Hz), 3.58 (dd,1H, J=11.6, 4.0 Hz), 3.84 (ddd, 1H, J=8.4, 5.9, 4.2 Hz), 5.10 (t, 1H,J=8.2 Hz), 5.67 (dd, 1H, J=15.4, 8.2 Hz), 5.90 (dt, 1H,. J=15.4, 6.7Hz);

[0794]¹³C NMR (75 MHz, CD₃OD) δ14.5, 23.8, 30.0, 30.2, 30.5, 30.6, 30.8,33.1, 33.3, 58.7, 62.2, 81.5, 124.4, 139.1, 168.1;

[0795] ESMS calcd for C₁₉H₃₅NO₃Na (M+Na) 348.3, found 348.2.

EXAMPLE 135

[0796](4S,5R)-4-(Fluoromethyl)-5-(n-pentadec-2′-enyl)-1,3-oxazolidinone, 139.

[0797] To a cold (−78° C.) solution of 138 (11.5 mg, 0.035 mmol) in THF(0.35 mL), DAST (14 μL, 0.106 mmol) was added. After stirring for 30min, the mixture was warmed up to room temperature and stirred for 2 h.The reaction was quenched with NaHCO₃ (5 mL), extracted with EtOAc (3×10mL), dried over Na₂SO₄ and concentrated in vacuo. The crude was purifiedby column chromatography, on silica (hexane/EtOAc 1:1) to obtainfluoride 139 as a white solid (7.5 mg, 65% yield).

[0798] R_(f) 0.22 (hexane/EtOAc 1:1);

[0799]¹H NMR (300 MHz, CDCl₃) δ0.88 (t, 3H, J=7.0 Hz), 1.20-1.40 (m,22H{), 2.09 (q, 2H, J=6.9 Hz), 4.03-4.13 (m, 1H), 4.41 (dm, 2H, J=46.5Hz), 5.11 (t, 1H, J=7.9 Hz), 5.44 (br s, 1H), 5.48 (dd, 1H, J=15.3, 8.1Hz), 5.95 (dt, 1H, J=15.3, 7.0 Hz);

[0800]¹³C NMR (75 MHz, CDCl₃) δ14.1, 22.6, 28.6, 29.1, 29.3, 29.4, 29.5,29.6, 31.9, 32.2, 55.3 (d), 79.0 (d), 81.8 (d), 121.4, 139.4, 159.3;

[0801] ESMS calcd for C₁₉H₃₄FNO₂Na (M+Na) 350.3, found 350.2.

EXAMPLE 136

[0802] (2S,3R)-2-Amino-1-fluoro-octadec-4-en-3-ol, 140.

[0803] To a solution of 139 (46 mg, 0.140 mmol) in dioxane (2.5 mL),NaOH (1M, 1.40 mL, 1.405 mmol) was added. After stirring for 4 h at 100°C., the reaction was quenched with H₂O (10 mL), extracted with EtOAc(3×10 mI), dried over Na₂SO₄ and concentrated in vacuo. The crude waspurified by column chromatography on silica (hexane/EtOAc 1:1 to 100%EtOAc) to obtain aminoalcohol 140 as a white solid (20 mg, 47% yield).

[0804] R_(f) 0.18 (hexane/EtOAc 1:5);

[0805]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.2 Hz), 1.20-1.40 (m,22H), 1.79 (br s, 3H), 2.05 (q, 2H, J=6.9 Hz), 3.03-3.13 (m, 1H), 4.05(t, 1H, J=6.4 Hz), 4.40 (ddd, 1H, J=47.5, 9.2, 6.9 Hz), 4.51 (ddd, 1H,J=47.0, 9.2, 4.2 Hz), 5.44 (dd, 1H, J=15.6, 7.4 Hz), 5.76 (dt, 1H,J=15.4, 6.9 Hz);

[0806]¹³C NMR (75 MHz, CDCl₃) δ14.1, 22.7, 29.1, 29.2, 29.3, 29.4, 29.6,29.6, 31.9, 32.3, 55.2 (d), 73.1 (d), 85.2 (d), 128.4, 135.2;

[0807] ESMS calcd for C₁₈H₃₇FNO (M+H) 302.3, found 302.2.

EXAMPLE 137

[0808] (2S,3R)-2-Amino-1-fluoro-3-octadecanol, 141.

[0809] According to the method of Example 89, from olefin 140 (4 mg,0.013 mmol), aminoalcohol 141 was obtained as a white solid (1.8 mg, 45%yield).

[0810]¹H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H, J=6.7 Hz), 1.20-1.40 (m,26H), 1.50-1.60 (m, 2H), 1.87 (br s, 3H), .3.04-3.14 (m, 1H), 3.54-3.62(m, 1H), 4.40 (ddd, 1H, J=48.0,: 9.2, 7.4 Hz), 4.56 (ddd, 1H, J=46.8,9.2, 3.9 Hz);

[0811]¹³C NMR (75 MHz, CDCl₃) δ14.1, 22.7, 26.0, 29.3, 29.6, 29.7, 31.9,32.9, 55.0 (d), 72.5 (d), 85.1 (d);

[0812] ESMS calcd for C₁₈H₃₉FNO (M+H) 304.3, found 304.3.

1. A compound of formula:

wherein: each X is the same or different, and represents H, OH, OR′, SH,SR′, SOR′, SO₂R′, NO₂, NH₂, NHR′, N(R′)₂, NHC(O)R′, CN, halogen, C(═O)H,C(═O)CH₃, CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈ alkyl,substituted or unsubstituted C₂-C₁₈ alkenyl, substituted orunsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaromatic, or two groups X maytogether form ═O; Y is NR₁, OR₁, PR₁, SR₁, or halogen, wherein thenumber of substituents R₁ is selected to suit the valency and each R₁ isindependently selected of H, OH, C(═O)R′, P(═O)R′R″, S(═O)R′R″,substituted or unsubstituted C₁-C₁₈ alkyl, substituted or unsubstitutedC₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈ alkynyl, substitutedor unsubstituted aryl, and wherein the dotted line indicates an optionaldouble bond such that Y can also be ═O or ═N—OH or the group Y withNR₂R₃ and the intervening atoms can form a heterocycle; each Z is thesame or different, and represents H, OH, OR′, SH, SR′, SOR′, SO₂R′, NO₂,NH₂, NHR′, N(R′)₂, NHC(O)R′, CN, halogen, C(═O)H, C(═O)CH₃, CO₂H,CO₂CH₃, substituted or unsubstituted C₁-C₁₈ alkyl, substituted orunsubstituted C₂-C₁₈ alkenyl, substituted or unsubstituted C₂-C₁₈alkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaromatic, or two groups Z may together form ═O; z is 0 to 25; y isQ to 20; R₂ and R₃ are the same or different and each is H, C(═O)R′,C(═S)R′, P(═O)R′R″, S(═O)R′R″, S(═O)₂R′, substituted or unsubstitutedC₁-C₁₈ alkyl, substituted or unsubstituted C₂-C₁₈ alkenyl, substitutedor unsubstituted C₂-C₁₈ alkynyl, substituted or unsubstituted aryl; eachof the R′, R″ groups is independently selected from the group consistingof H, OH, NO₂, NH₂, NHR′, NR′R″, SH, CN, halogen, ═O, C(═O)H, C(═O)CH₃,CO₂H, CO₂CH₃, substituted or unsubstituted C₁-C₁₈ alkyl, substituted orunsubstituted C₁-C₁₈ alkoxy, substituted or unsubstituted C₂-C₁₈alkenyl, substituted or unsubstituted C₂-C₁₈ alkynyl, substituted orunsubstituted aryl; there may be one or more unsaturations in thehydrocarbon backbone defined by the chain:

and salts thereof; with the exception of a C₁₆-C₂₄2-amino-3-hydroxyalkane or a C₁₆-C₂₄ 2-amino-3-hydroxyalkene.
 2. Acompound or salt according to claim 1, wherein the hydrocarbon backbonedefined by the chain:

is of the formula: where x is 0 to 20 and the dotted line indicates oneor more double bonds in the backbone.
 3. A compound or salt according toclaim 2, wherein there is a double bond at the position shown by thedotted line.
 4. A compound or salt according to any preceding claim,wherein the terminal group —C(X)₃ is —CH₃.
 5. A compound or saltaccording to any preceding claim, wherein there are no unsaturations inthe hydrocarbon backbone.
 6. A compound or salt according to claim 2 ora claim dependent thereon, wherein the hydrocarbon backbone is of theformula:

where x and y are as defined.
 7. A compound or salt according to anypreceding claim, wherein z is from 10 to
 19. 8. A compound or saltaccording to any preceding claim, wherein Y is OH, O(C═O)R′ where R′ isoptionally halogen-substituted alkyl, OR′ where R′ is alkyl, halogen,OP(═O)R′₂ where R′ is alkoxy, NH₂, ═O, ═NOH, or the group Y when OH withNR₂R₃ and the intervening atoms form a heterocycle of formula:


9. A compound or salt according to any preceding claim, wherein R₂ andR₃ are the same.
 10. A compound or salt according to any precedingclaim, wherein at least one of R₂ and R₃ is alkyl; alkyl substituted byaryl; hydrogen; C(═O)R′ where R′ is alkyl or alkoxy, halogen-substitutedalkyl, optionally substituted amino-substituted alkyl, aryloxy,, alkoxy,optionally substituted aryl-substituted alkenyl; (C═S)NHR′ where R′ isaryl; (C═O)NHR′ where R′ is aryl or alkyl; SO₂R′ where R′ is alkyl, or(C═O)R′ where R′ is optionally substituted aminoalkyl thereby giving anoptionally substituted aminoacid acyl group.
 11. A compound or saltaccording to any preceding claim, wherein y is 0 to
 3. 12. A compound orsalt according to any preceding claim, wherein the terminal group —C(Z)₃is —CH₃.
 13. A compound or salt according to any preceding claim, whichhas the stereochemistry


14. A compound or salt according to any preceding claim, wherein two ormore of the following criteria are met: the terminal group —C(X)₃ is—CH₃; z is 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 the hydrocarbonbackbone is of the formula:

where x is 12; Y is OR₁ where R₁ is H, methyl, acetyl, PO(OMe)₂, COCF3or Y is Cl, NH₃ ⁺Cl—, ═O, ═NOH; R₂ and R₃ are independently selectedfrom the group consisting of H, methyl, acetyl, benzyl, Boc, CSNHPh,CONHPh, CONH^(n)Bu, SO₂Me, COCF₃, COCH═CHPh, COCH═CHPhCF₃, COC₁₅H₃₂,COCH(NHBoc)CHMe₂, COCH(NH₃ ⁺Cl—)CHMe₂; y is 0, 1, 2 or3; Z is the sameor different, and represents H, F, methyl, ethyl, hydroxyphenyl, amino,dibenzylamino or NH₃Cl; the stereochemistry is

or the compound or salt is in the form of a salt.
 15. A compound or saltaccording to claim 14, which meets one the following criteria: z is not12, 13 or 14; Y is not OH; At least one of R₂ and R₃ is not hydrogen; yis at least 1; at least one Z is not hydrogen; the compound or salt isin the form of a salt.
 16. A compound or salt according to any precedingclaim, which is of the formula:

where z is 10 to 19; Y is OR₁ where R₁ is H, methyl, acetyl, PO(OMe)₂,COCF₃ or Y is Cl, NH₃ ⁺Cl—, ═O, ═NOH; R₂ and R₃ are independentlyselected from the group consisting of H, methyl, acetyl, benzyl, Boc,CSNHPh, CONHPh, CONH^(n)Bu, SO₂Me, COCF₃, COCH═CHPh, COCH═CHPhCF₃,COC₁₅H₃₂, COCH(NHBoc)CHMe₂, COCH(NH₃ ⁺Cl—)CHMe₂; Z represents H, F,methyl, ethyl, hydroxyphenyl, amino, dibenzylamino or NH₃Cl.
 17. Acompound or salt according to any preceding claim, which is one of thefollowing compounds:


18. A pharmaceutical composition comprising a compound or salt accordingto any preceding claim, together with a pharmaceutically acceptablecarrier.
 19. The use of a compound according to any of claims 1 to 17 inthe preparation of a medicament for the treatment of a tumor.
 20. Amethod of treating a tumor which includes administration of an effectiveamount of a compound or salt according to any of claims 1 to 17, or acomposition according to claim 18.